Pleiotropic Functions of Neurotrophins in Development

Cytokine + Growth Factor Reviews Vol[ 8\ No[ 1\ pp[ 014Ð026\ 0887 Þ 0887 Elsevier Science Ltd[ All rights reserved

PII] S0248Ð5090"87#99992Ð2

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Pleiotropic Functions of Neurotrophins in Development

Lino Tessarollo Neurotrophins are soluble growth factors known mainly for their roles in regulating the development of the mammalian nervous system[ Two types of receptors mediate the actions of these polypeptides] the Trk family of tyrosine kinase receptors and the so!called p64 low!af_nity NGF receptor[ Neurotrophins and their receptors are highly expressed in the nervous system[ Gene targeting approaches in the mouse have uncovered some of their functions in promoting survival and devel! opmental maturation of certain types of neurons of the peripheral and central nervous system\ con_rming their critical role in neural development[ Furthermore\ the phenotypes observed in these mutants have demonstrated the speci_city of the interactions between neurotrophins and their receptors[ These families of genes are also widely expressed in a variety of non!neuronal systems throughout development\ including the cardiovascular\ endocrine\ reproductive and immune systems[ Our knowledge of neurotrophin functions in non!neuronal tissues is still fragmented and mostly indirect[ Nevertheless\ there is increasing evidence that neurotrophins may have broader physiological effects besides regulating neuronal survival and differentiation[ Analysis of mice lacking neu! rotrophins or neurotrophin receptors promises to provide avenues for elucidating these functions[ Þ 0887 Elsevier Science Ltd[ All rights reserved[

Key words] Trk = Neurotrophin = Gene targeting = Neuronal = Non!neuronal[

INTRODUCTION Neurotrophins belong to a highly homologous family of secreted growth factors that have been extensively studied for their roles in proliferation\ survival and di}erentiation of di}erent cell populations in the mammalian nervous system ð0Ł[ This family includes nerve growth factor "NGF#\ brain!derived neurotrophic factor "BDNF#\ neurotrophin!2 "NT!2# and neurotrophin!3:4 "NT3:4# ð1Ł[ Two types of receptors mediate the action of these polypeptides] the Trk family of tyrosine kinase receptors\ to which neurotrophins bind with high a.nity and the p64 low!a.nity NGF receptor "LANR#\ a member of

To whom all correspondence should be addressed] Dr L[ Tessarollo\ Neural Development Group\ ABL!Basic Research Program\ NCI!FCRDC\ Frederick\ MD 10691\ U[S[A[ Tel[] 290!735!0191^ Fax] 290!735!5555^ E!mail] tessarolÝncifcrf[gov By acceptance of this article\ the publisher or recipient acknowledge the right of the U[S[ Government and its agents and contractors to retail a non!exclusive royalty!free license in and to any copyright covering the article[

the tumor necrosis factor receptor family ð2Ð4Ł[ Binding experiments with cell lines were used to determine the ligand!receptor relationship between neurotrophins and their receptors ð3Ł[ NGF binds only to TrkA\ whereas BDNF and NT3:4\ growth factors with dissimilar pat! terns of expression\ bind to TrkB[ NT!2 signals mainly through TrkC but can also bind with lower a.nity to TrkA and TrkB and can signal\ in some cellular environ! ments\ through these receptors "Figure 0# ð1Ł[ Neuro! trophins bind and dimerize their speci_c Trk receptors^ dimerization activates the receptor!intrinsic tyrosine kinase\ resulting in autophosphorylation of several tyro! sine residues within the receptor|s cytoplasmic domain[ Several cytoplasmic signaling molecules*for example\ phospholipase!Cg\ phosphatidyl inositol!2? kinase and adaptor proteins such as SHC*then bind to these phos! photyrosine!containing recognition sites and trigger kin! ase cascades that culminate in the activation of transcription factors and a variety of cellular responses ð3\ 5\ 6Ł[ The trkB and trkC loci encode receptors lacking the kinase domain\ in addition to the well!studied full! length tyrosine kinase receptors[ However\ very little is known about the function of these truncated receptors

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L[ Tessarollo

or the mechanism by which they mediate neurotrophin activities ð7Ð00Ł[ All neurotrophins also interact with p64[ The physio! logical role of this receptor is also unclear although it has been shown to in~uence high!a.nity NGF receptor formation and ligand internalization[ LANR lacks intrin! sic enzymatic activity but is able to activate signal trans! duction pathways[ For example\ in _broblasts\ p64 mediates ceramide production by sphingomyelin hydrolysis and in Schwann cells\ upon binding NGF\ can induce translocation to the nucleus of the transcription activator NF!kB which has been linked to induction of apoptosis ð01Ð03Ł[ A major contribution to understanding the in vivo func! tions of neurotrophins has come from the study of the distribution of neurotrophins and their receptors in embryonic and adult tissues of di}erent animal species[ These studies\ in combination with in vitro and in vivo assays\ have helped to determine which cell types are the likely targets of neurotrophin action[ In addition\ the availability of genetically engineered mouse models obtained by targeted deletion of neurotrophins or their receptors has provided a new means to test the early hypotheses on neurotrophin functions ð0\ 04Ł[ This article will present some of the results obtained by the analysis of these mutant mice in relation to neu! rotrophin and neurotrophin receptor localization studies[ Special emphasis will be given to the variety of functions that these molecules may play outside the nervous system[ CONTROL OF BIOLOGICAL ACTIVITIES Several mechanisms\ such as spatio!temporal control of neurotrophin and receptor isoform expression\ have been proposed to explain the speci_c actions of neu! rotrophins and their receptors[ It is also becoming increasingly clear that the speci_c cellular environment greatly in~uences the mode of neurotrophin activity ð05\ 06Ł[ Although the majority of studies addressing the molecular mechanisms have focused on neuronal cell types\ neurotrophins and their receptors function in non! neuronal tissues as well[ Spatio-temporal control of receptor expression Studies of neurotrophin receptor localization have extended our view of the complexity of potential roles that neurotrophins play in development[ Upon their initial cloning\ it became apparent that these classes of receptors are expressed at the highest levels in the per! ipheral nervous system "PNS# and central nervous system "CNS#] trkA is localized in the peripheral sensory neurons\ including dorsal root ganglia "DRG# and sym! pathetic ganglia and in the CNS\ in the cholinergic neu! rons of the basal forebrain ð07\ 08Ł[ TrkB and trkC are found throughout the developing nervous system\ includ! ing almost all regions in the brain\ spinal cord and cranial and spinal ganglia ð19Ð13Ł[ More systematic and detailed studies of neurotrophin receptor localization revealed sig!

ni_cant levels of expression of the high!a.nity Trk recep! tors in tissues outside the nervous system\ establishing non!neuronal tissues as additional targets of neu! rotrophin action "see below and ð12\ 14Ð16Ł#[ Also\ p64 LANR expression in rats is widespread both during embryonic development and in the adult ð17\ 18Ł[ Highest levels of this receptor have been identi_ed in both the PNS and CNS^ however\ almost all non!neuronal tissues analysed also express some amounts of this recep! tor\ including Sertoli cells\ the developing kidney and some cell populations of the immune system ð29Ð21Ł[ The well established role of neurotrophins as target derived survival factors illustrates how the spatial expression of the neurotrophins and their receptors can in~uence function[ During development\ many neurons die shortly after their axons innervate the target area such that the number of neurons would match the size of the target area ð22Ł[ Di}erential expression of neurotrophins within a certain region also provides a means for speci! _city of innervation by functionally distinct neurons expressing di}erent trk receptors[ Recent studies of the sites of neurotrophic factor synthesis have implied that neurotrophic support may be obtained from sources other than axonal targets[ These include cells located along the length of the axon\ or within the vicinity of the neuronal cell body or dendritic arbor[ Moreover\ BDNF has been shown to exhibit autocrine e}ects within some populations of developing neurons ð23\ 24Ł[ Finally\ ante! rograde axonal transport of neurotrophins has been dem! onstrated in vivo\ suggesting that some neurons receive trophic support through a}erent innervation ð25Ð27Ł[ In addition to the spatial distribution\ the temporal pattern of expression of neurotrophins and their recep! tors is regulated\ ensuring very restricted interactions of neurotrophins with neurons that may have a broad spec! trum of neurotrophin responsiveness[ For example\ some neurons in the CNS express both trkB and trkC receptors\ suggesting that control of neurotrophin expression deter! mines neuronal survival and:or di}erentiation responses[ Alternatively\ di}erent neurotrophins could have addi! tive or distinct functions in the same cell ð28\ 39Ł[ Exam! ples of temporal control of receptor expression have been well studied in speci_c populations of the PNS[ Sensory neurons from the nodose\ dorsal root and trigeminal ganglia are known to switch their neurotrophin depen! dency during development ð30Ł[ For instance\ early in development\ during neural crest migration and gan! gliogenesis\ DRG precursor cells express trkC and depend on NT!2 for their survival and proliferation ð31Ł[ Later\ after gangliogenesis and neuronal di}erentiation\ the majority of these neurons express the trkA receptor and switch their dependency to NGF ð32\ 33Ł[ Alternative splicing mechanisms All trk loci generate receptor isoforms by alternative splicing "Figure 0# ð05\ 34Ð38Ł[ The trkA locus encodes two isoforms that di}er only by an 07!bp insertion in the

Pleiotropic Functions of Neurotrophins in Development

extracellular domain[ In _broblasts\ the presence "trkA II# or absence "trkA I# of the 5!amino acid insert does not a}ect the receptor|s ligand!binding speci_city or its ability to transduce the signal in response to NGF[ How! ever\ in a neuronal cell line\ trkA II displays signi_cantly higher activation by NT!2 ð49Ł[ The two trkA isoforms are distributed in a tissue!speci_c manner] the nervous system expresses almost exclusively trkA II\ whereas non! neuronal tissues express both isoforms[ These data sug! gest that some cell types use alternative splicing to pro! duce trkA isoforms with di}erent receptor!binding speci_city and with de_ned developmental functions ð36\ 49Ł[ While the trkA locus encodes receptors with variations in the extracellular domain\ the trkB and trkC loci encode receptors that di}er in the cytoplasmic domain ð05\ 34\ 35\ 37\ 38Ł[ In particular\ both encode full!length kinase! active receptors as well as truncated receptors that lack intrinsic kinase activity[ In addition\ trkC can generate isoforms with insertions at the major autophosphory! lation site of the catalytic domain "Figure 0^ ð05\ 37\ 40Ł#[ Comparison of signaling potentials between the kinase isoforms with insertions and the full!length tyrosine kin! ase receptors have shown that trkC!insert isoforms have a low signaling capability in a neuronal cell line[ It has been hypothesized that these kinase!insert receptors could modulate signal transduction either by formation of heterodimers with full!length trkC or by competitive binding of neurotrophin[ However\ since the trkC!kinase insert isoforms have a higher signaling capability in a _broblast cell line compared with the neuron!like PC 01 cell line\ it is possible that these receptors\ depending on the cellular environment\ have distinct functions in vivo ð40Ð42Ł[ The role of truncated trkB and trkC receptors lacking the kinase domain still remains elusive[ Experimental data have led to the development of several models that suggest functions for this type of receptors[ The expression of truncated trkB by astrocytes\ oligo! dendrocytes and Schwann cells and the altered levels in response to injury suggests that glial truncated trkB receptors may serve in augmenting or reducing the levels of neurotrophins available to nerve cells\ depending on their particular physiological status ð43\ 44Ł[ Similarly\ the distribution of truncated receptors in non!neuronal tissues in vivo supports a mechanism by which seques! tering of soluble neurotrophic factor may regulate the amount of neurotrophin interacting with the kinase! active receptor ð37\ 45\ 46Ł[ However\ results obtained by co!expressing full!length and truncated trkB receptors in Xenopus oocytes and sympathetic neurons have suggested that truncated receptors can also act as naturally occur! ring dominant negative elements of the full!length recep! tor ð7\ 8Ł[ Alternatively\ up!regulation of truncated receptors in di}erentiated neurons of the adult brain has suggested that these receptors function in promoting neu! ronal di}erentiation or specify functional properties of mature neurons ð45\ 47\ 48Ł[ Furthermore\ the intra! cellular part of truncated trkB and trkC receptors harbors

016

domains that are highly conserved between species\ sug! gesting the functional importance of binding sites for signaling molecules ð09\ 05\ 37\ 38Ł[ In fact\ truncated trkB receptors have demonstrated a signaling capability by promoting a ligand!mediated increase in the rate of acidic metabolite release from the cell\ a common physio! logical consequence of many signaling pathways[ Although there is no indication on the type of pathway involved\ this represents a very intriguing result ð09Ł[ It is important to note that a signaling mechanism and action as a dominant!negative or sequestering e}ector do not have to be mutually exclusive functions[ The variety of isoforms produced by the trk loci and the complex patterns of expression during ontogenesis suggest that several mechanisms are used to control the multiplicity and speci_city of neurotrophin functions[ By di}erential expression or co!localization of these recep! tors\ speci_c cell types may increase their range of neu! rotrophin responsiveness and either integrate or superimpose di}erent neurotrophin functions\ providing the cell with unique developmental potentials[ KNOCKOUT MOUSE MODELS Expression data and functional data obtained by in vitro studies have emphasized the complexity of activities that neurotrophins may exert during development[ How! ever\ while such studies have laid the foundation for understanding where and how neurotrophins act\ these approaches do not have a direct bearing on neurotrophin function in vivo[ Recently\ animal models lacking func! tional neurotrophins or their receptors have been gener! ated\ thus helping to _ll some of these gaps ð00\ 04\ 32\ 59Ð54Ł[ Neurotrophins are encoded by single exons[ Therefore\ either deletion of the coding sequence or inser! tional disruption of the reading frame has been used to inactivate these genes[ The trk receptor genes\ however\ contain multiple exons that generate di}erent isoforms by alternative splicing ð59Ł[ The exons encoding the trunc! ated receptor isoforms are located upstream of the kinase domain region[ Since targeting of trkA\ trkB and trkC has initially been performed at the kinase domain\ it is possible that the trkB and trkC loci are still capable of generating truncated receptors ð55Ð57Ł[ Indeed\ a second mutant mouse in which all trkC isoforms have been deleted develops a more severe phenotype than the mutant lacking the kinase domain\ suggesting that func! tional truncated receptors are still produced in the _rst strain "Table 0^ ð00Ł#[ Nevertheless\ analysis of the kinase mutant mouse provided insight into neurotrophin func! tion in vivo\ proving some of the original predictions about neurotrophin requirements for speci_c neuronal populations and ligand!receptor interactions[ All neu! rotrophins and their receptors\ except NT!3:4 and p64\ are essential for postnatal life\ since homozygous mutant mice die perinatally or in the _rst few weeks after birth[ The severity of the phenotypes observed suggests that a variety of organ systems fail due to the lack of neu! rotrophin signaling[

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L[ Tessarollo

Figure 0[ Schematic representation of Trk and p64 receptors and their ligand!binding speci_cities with neurotrophins[ Dimeric neurotrophic factors "NGF\ nerve growth factor^ BDNF\ brain!derived neurotrophic factor^ NT!2\ neurotrophin!2 and NT!3:4\ neurotrophin!3:4# are represented by two circles or ovals[ Neurotrophins bind to their receptors with high a.nity "bold arrows# or low a.nity "thin arrows#[ All the isoforms of TrkA "I\ II#\ TrkB "FL\ full!length^ TK!T0 and T1 tyrosine kinase truncated# and trkC "FL\ full!length^ TK!T0 and T1 tyrosine kinase truncated^ 03\ 14\ 28 tyrosine kinase domain with inserts# contain the predicted motifs in their extracellular domain] the amino "NH1 CRR# and carboxy "COOH!CRR# cysteine!rich regions\ the leucine!rich region and the two immunoglobulin!like domains "Ig 0 and Ig 1#[ The small box in the extracellular domain\ next to the transmembrane domain region "TM# of the TrkA II receptor\ represents the small insertion speci_c for this isoform[ The extracellular domain of the p64 receptor contains the four cysteine!rich domains "CRD# indicated by ovals[ In the cytoplasmic region\ the full boxes of trkA I and II\ TrkB FL and TrkC FL indicate the tyrosin kinase domain[ TrkC 03\ 14 and 28 have small inserts in the tyrosine kinase domain box[ The small boxes in the TrkB TK!T0 and T1 and TrkC TK!T0 and T1 represent the distinctive non!catalytic intracellular domains of the truncated "TK# receptor isoforms[ The signaling capability of the receptors is indicated by arrows below the intracellular region of the receptor[ Compared to the full!length isoforms "bold arrows#\ the kinase!insert isoforms display reduced signaling capability "thin arrows#[ The signaling mechanism of the truncated receptors are not known "open arrows#[ The hatched arrow indicates that the p64 receptor can signal independently of Trk receptors[

PNS deficiencies Both NGF !:! and trkA !:! "knockout# mice have simi! lar phenotypes[ Ablation of either gene results in the virtual absence of the superior cervical ganglia "SCG# neurons by the _rst postnatal week\ con_rming the criti! cal role of NGF:trkA signaling for the development of sympathetic neurons[ Furthermore\ both types of mice are insensitive to pain\ due to the loss of small!diameter nociceptive sensory neurons ð57\ 70Ł[ Strikingly\ human patients with congenital insensitivity to pain were shown to have inactivating mutations in the trkA gene ð72Ł[

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Thus\ trkA or NGF mutant mice may provide a model for the study of this human disease[ A direct comparison between BDNF and trkB knock! out mice is di.cult because of the presence of another physiologically relevant ligand\ NT!3:4[ In addition\ the expression of trkB truncated isoforms probably persists in the trkB mutant animal\ adding to the complexity of the overall phenotype of trkB !:! mice[ However\ both trkB and BDNF mutant mice display similar behavioral phenotypes associated with spinning and balance de_ciencies consistent with abnormalities of the ves! tibular system[ In fact\ either mutation produces severe

)

018 Mice with single or double gene deletions were analysed[ The PNS data represents ) neuronal losses\ compared to controls\ of trigeminal\ geniculate\ vestibular\ coclear\ petrose! nodosal\ dorsal root "DRG# and superior cervical "SCG# ganglia[ trkBkin and trkCkin indicate targeting in the kinase domain region of the gene[ trkCall indicates that all trkC isoforms were deleted in this mutant mouse[ nd\ not determined[ References are in brackets[

19Ð29 ð61\ 62Ł 84 ð62Ł 71 ð62Ł nd 89 ð61\ 62Ł nd 9 ð62Ł nd 87 ð64Ł 099 ð64Ł 099 ð64Ł 84 ð64Ł 30 ð64\ 65Ł nd 51 ð50\ 63Ł 24 ð50\ 63Ł 29Ð24 ð50\ 63Ł 74 ð50\ 63Ł 24 ð50\ 63Ł 54Ð69 ð50\ 63Ł 49 ð50\ 63Ł 9 ð61\ 62Ł 49 ð62Ł 9 ð62\ 67Ł nd 49 ð61\ 62Ł 0 4 ð62Ł 9 ð62Ł 05 ð69\ 60Ł 39 ð69\ 60Ł 79Ð87 ð69\ 60Ł 9Ð4 ð69\ 60Ł 49 ð79Ł 29 ð69\ 60Ł 9 ð69\ 60Ł nd nd nd nd nd 69 ð70Ł 89 ð70Ł 10 ð00Ł 00 ð00Ł 04 ð00Ł 69 ð00Ł 04 ð00Ł 22 ð00Ł 9 ð00Ł 11 ð58Ł 19 ð64Ł 05 ð64\ 66Ł 49Ð54 ð64\ 66Ł 07 ð64\ 79Ł 06 ð56\ 65Ł 9 ð71Ł 22 ð58Ł 74 ð64Ł 59Ð79 ð64\ 66Ł 04Ð19 ð64\ 66Ł 84 ð64\ 79Ł 19 ð65Ł 9 ð71Ł PNS de_ciencies trigeminal 69 ð58Ł geniculate nd vestibular 9 ð65Ł coclear 9 ð65Ł petr[!nod[ nd DRG 69Ð79 ð57\ 65Ł SCG 84 ð71Ł

NT!2 9Ð0 day NT!3:4 normal BDNF 1Ð3 wk NGF 1Ð3 wk trkCall 0Ð3 days trkCkin 1Ð3 wk trkBkin 1Ð3 wk trkA 1Ð3 wk Mutant strain Viability

Contrary to the results obtained in the PNS where neurotrophin signaling is required for the development of sensory and sympathetic ganglia\ analysis of the CNS in newborn mice lacking neurotrophins or their receptors revealed only mild neuronal losses ð04Ł[ These results suggested that neurotrophins do not play a major role in the survival and di}erentiation of CNS neurons during embryonic development[ However\ other pathways involving other classes of factors and their receptors\ such as ephrins and Eph receptors\ are critical for the embryonic development of CNS neurons ð73Ł[ Many CNS neurons\ including basal and striatal chol! inergic neurons\ mature during the early postnatal period ð74Ł[ Initial analysis of newborn NGF! or trkA!de_cient mice did not indicate reduced numbers of basal chol! inergic neurons but did show phenotypic changes\ such as reduced levels of choline acetyltransferase ð57\ 70Ł[ However\ analysis of 3!week!old trkA!de_cient animals showed signi_cantly fewer and smaller cholinergic neu! rons in both the striatum and septal regions\ as compared with controls\ suggesting that trkA:NGF signaling is required for normal maturation of these neurons ð75Ł[ De_ciencies were also observed in the maturing CNS of trkB or trkC mutant animals[ Elevated levels of apoptotic cell death were reported in the dentate gyrus\ cortex\ striatum and thalamus of trkB mutant mice in the _rst postnatal weeks ð76Ł[ This defect is much more dramatic in the dentate gyrus of trkB and trkC double!mutant mice\ suggesting that trkB and trkC have additive func! tions when expressed in the same cell ð39\ 77\ 78Ł[ In BDNF!de_cient mice\ increased death of cerebellar gran! ule cells results in abnormal cerebellar development and foliation\ indicating that neurotrophins also play critical functions in CNS patterning ð89Ł[

Table 0[ Viability and peripheral nervous system "PNS# de_ciencies of mice lacking neurotrophins or their trk receptors

CNS deficiencies

trkBkin trkCkin BDNF NT!3:4 BDNF NT!2 0Ð4 days 1Ð3 wk 9 days

defects in the vestibular ganglia ð69\ 60\ 66Ł[ Interestingly\ BDNF and NT!3:4 double mutations cause PNS losses comparable to the ones produced by the trkB mutation\ con_rming the in vivo relevance of the same receptor system to both neurotrophins "Table 0#[ NT!2 and kinase!mutant trkC "trkC kinase !:!# knock! out mice are quite di}erent\ even though both exhibit the same de_ciencies in movement and posture due to proprioception defects and loss of large!diameter muscle a}erents projecting to the ventral horn of the spinal cord[ Neuronal counts on spinal sensory ganglia have shown that the loss of neurons is greater in NT!2 !:! than in trkC kinase !:! mice ð32\ 50\ 51\ 56\ 63Ł[ Similarly\ NT!2 !:! mice exhibit severe sympathetic defects\ whereas in the trkC kinase!mutant mice no de_ciencies have been reported in the SCG ð71Ł[ Even though mutant mice in which all trkC receptors\ including the truncated ones\ have been deleted display more neuronal losses than the kinase!mutant mice\ the phenotype is still less severe than in the NT!2 knockout mice[ These data suggest that NT! 2 acts in vivo through other receptors ð00Ł[

63 ð54Ł 54 ð54Ł 099 ð54\ 68Ł 099 ð54\ 68Ł 51 ð54Ł 72 ð54Ł nd

Pleiotropic Functions of Neurotrophins in Development

029

L[ Tessarollo

The expression of abundant levels of neurotrophins and their receptors in the CNS throughout adult life suggests that in addition to their role in development\ neurotrophins continue to function in the mature nervous system[ It has been postulated that neurotrophin sig! naling in the postnatal CNS may play a role in promoting the survival and:or regrowth of neurons following injury or in neurodegenerative disorders "reviewed in ð80Ð82Ł#[ The axotomy of facial nerve motor neurons paradigm has been experimentally examined in the trkB de_cient mouse model[ Following facial nerve transaction\ motoneuron loss was found to be augmented in this mouse compared to controls suggesting that trk! :neurotrophin signaling supports CNS neurons after injury ð76Ł[ Another functional role for neurotrophins in the mature CNS that has recently gained attention is in the activity dependent modulation of synaptic plasticity ð83\ 84Ł[ For example\ expression of neurotrophins and their receptors persists in the adult hippocampus and can be regulated by neuronal activity[ In addition\ neu! rotrophins modulate the establishment of long!term potentiation "LTP# in hippocampal slides*a form of synaptic plasticity associated with learning and memory formation[ In agreement with these results\ analysis of BDNF mutant mice showed a signi_cant impairment in hippocampal LTP that can be rescued by acute treatment with exogenous BDNF ð52\ 85\ 86Ł[ Similarly\ mice lack! ing one NGF allele show memory de_ciencies that can be partially corrected by intraventricular infusion of recombinant NGF ð87Ł[ These data suggest that a major role of neurotrophins in the adult brain is the modulation of neuronal activity[

The following is an overview of some of the information available on neurotrophin functions in non!neuronal sys! tems[ Reproductive system Animals lacking neurotrophins or their receptors\ with the exception of p64! and NT!3:4!de_cient animals\ have not yet been tested for reproductive defects\ mainly because of the early perinatal lethality associated with these mutations "Table 0#[ Most of the data indicate that neurotrophins may play a role in gonadal functions unrelated to the support of gonadal innervation[ Expression analyses have revealed the presence of all trk receptors in the developing testis\ although their func! tional signi_cance has not been further investigated ð16\ 37\ 029Ł[ In the mammalian ovary\ trkA is expressed in the theca\ which surrounds mature follicles[ In vitro experiments suggest that NGF acts on thecal cells\ dis! rupting cell!to!cell communication by a}ecting the func! tional integrity of gap junctions preceding ovulation ð016\ 020Ł[ Immunological blockade of NGF functions or trkA transducing activity inhibits ovulation\ suggesting that activation of the NGF:trkA complex in non!neuronal cells of the periovulatory follicle is a physiological com! ponent of the ovulatory cascade ð021Ł[ Other neur! otrophins\ including NT!2 and NT!3:4 and neurotrophin receptors\ including p64 and trkB\ are developmentally regulated in the mature mammalian ovary\ although their functional role in this organ has not yet been investigated ð020Ł[ Endocrine system

NEUROTROPHIN FUNCTIONS OUTSIDE THE NERVOUS SYSTEM Several laboratories have described the e}ects of NGF on a variety of non!neuronal cellular systems "Table 1#[ However\ reports on e}ects by other neurotrophins remain scarce[ The reason for this disproportion of data is probably due to two factors[ First\ NGF is the prototypic neurotrophic factor\ isolated more than 39 years ago\ whereas the other neurotrophins were discovered much later "BDNF in 0871 and NT!2 and NT 3:4 in the 0889|s#[ Second\ NGF has been available in pharmacological amounts even before molecular cloning technology allowed for the production of recombinant neurotrophins ð018Ł[ In the mouse models lacking neurotrophins or their receptors\ very little attention has been given to the analy! sis of structures outside the nervous system\ despite numerous reports describing the detection and possible roles of these molecules in non!neuronal tissues[ The only reports of such functions involve mice lacking NT!2 or its trkC receptor\ which showed the requirement of this ligand:receptor system for the normal development of cardiac atria\ ventricles and out~ow tracts "see later#[

The concept of NGF as a modulator of neuroendocrine functions came from the initial observation that it could activate the pituitary!adrenocortical axis with a con! comitant enhancement of serum glucocorticoid con! centration ð022\ 023Ł[ More recently\ several laboratories have detected the presence of neurotrophins and their receptors in several structures of the endocrine system[ For example\ it has been reported that the pituitary\ including its non!neural anterior lobe\ expresses BDNF\ trkB and trkC and their expression levels change with aging ð024\ 025Ł[ Furthermore\ in vitro studies have shown that NGF promotes the di}erentiation of bipotential pre! cursor cells to the mammotroph phenotype during pitu! itary development\ suggesting that the acquisition of speci_c phenotypes by this gland is under neurotrophic control "Table 1^ ð013Ł#[ Trk receptors are also expressed in the endocrine com! ponent of the rat and human pancreas\ although some di}erences between the two patterns of expression exist ð026\ 027Ł[ In the rat\ trkB is expressed in glucagon! secreting a!cells and trkC is present in a! and insulin! secreting b!cells[ Furthermore\ rat primary b!cells con! tain trkA receptors and an insulin!secreting cell line expresses functional trkC receptors\ suggesting that the

Pleiotropic Functions of Neurotrophins in Development

020

Table 1[ Effects of NGF and NT!2 on cell types outside the nervous system Cell type

E}ect

References

B!lymphocytes

survival proliferation di}erentiation regulation of Ig production activation activation survival cytotoxicity survival growth di}erentiation activation chemotaxis di}erentiation activation degranulation survival di}erentiation activation degranulation regulation of Na¦!channels migration proliferation proliferation di}erentiation migration di}erentiation survival "# proliferation di}erentiation di}erentiation ovulation steroid secretion"#

ð88Ł ð21\ 88\ 099Ł ð21\ 099Ł ð090\ 091Ł ð092Ł ð093Ł ð094Ł

T!lymphocytes Monocytes Eosinophils Neutrophils

Basophils Mast cells

Skeletal muscle cells Vascular smooth muscle cells Keratinocytes Chroma.n cells Melanocytes Pituitary cells Pancreatic b!cell line Ovarian thecal cells Ovarian follicles

ð095Ł ð096Ł ð096Ł ð095Ł ð097Ł ð096\ 098Ł ð009Ł ð000Ł ð001\ 002Ł ð003Ł ð001Ł ð004\ 005Ł ð006Ł ð007Ł ð008Ł ð019Ł ð010\ 011Ł ð012Ł ð013Ł ð014\ 015Ł ð016Ł ð017Ł

"# Responses triggered by NT!2[

endocrine component of the pancreas may represent a target for neurotrophin action ð026\ 028Ł[ Lastly\ ovary!secreted neurotrophins have been impli! cated in the regulation of gonadal endocrine activities[ In fact\ TrkC is produced in steroid!producing thecal and granulosa cells and NT!2 has been shown to augment steroid secretion by hamster ovarian follicles in vitro ð016\ 017Ł[ Cardiovascular system The cardiovascular system is another non!neuronal site where neurotrophins and their receptors are expressed ð039Ł[ Of these genes\ the best!characterized is the NT!2: trkC ligand!receptor complex[ Initial results from expression analysis in the cardiovascular system sug! gested that these factors support abundant innervation\ similar to that found in other systems ð030Ł[ However\ the detection of TrkC in mouse cardiac myocytes and migrating cardiac neural crest cells long before inner! vation occurs suggests that diverse roles are played by neurotrophins and their receptors in the development of the cardiovascular system ð12\ 031Ł[ The observations that neurotrophins have chemotactic activity on vascular

smooth muscle cells ð007Ł and melanocytes ð011Ł are suggestive of additional neurotrophic functions[ More de_nitive data in support of a direct role for trkC and NT!2 in cardiovascular development have been obtained from the analysis of mice de_cient for these gene products[ Mice lacking NT!2 develop with abnor! malities of the great vessels\ including developmental delay in the primitive myo_bril organization of the trun! cus arteriosis\ as early as embryonic day 8[4 ð031Ł[ These defects are associated with reduced levels of expression of trkC in myocytes within the ventricles\ atria and cardiac out~ow tracts[ Furthermore\ these early developmental defects before the onset of cardiac innervation are con! sistent with a direct role of NT!2 and trkC in cardiac development[ More striking defects were observed in the atria\ ventricular septation\ valves\ and out~ow tracts of both trkC and NT!2 mutant mice ð00\ 031Ł[ This pheno! type is consistent with abnormalities in the survival and:or migration of the cardiac neural crest early in embryogenesis[ Considering the wide contribution of the neural crest to a variety of structures during development\ it would not be surprising if other defects in non!neuronal neural crest!derived structures would be identi_ed upon further analysis of these two types of mutant mice[ Fur!

021

L[ Tessarollo

thermore\ the possibility that other neurotrophins or their receptors play similar roles still remains open\ since BDNF also exerts some e}ects on isolated neural crest cells ð032Ł[ Immune system

critical functions of these genes in neural development[ They are essential for the embryonic development of spec! i_c classes of PNS neurons and contribute to the func! tional phenotype of CNS neurons[ By de_ning the neurotrophic requirements of speci_c cell types during development\ these studies should provide useful infor! mation for the potential therapeutic and clinical appli! cations of neurotrophins and their receptors in neurological disorders[ Furthermore\ these studies give insight into the mechanisms of speci_c side e}ects caused by neurotrophins in animal studies and clinical trials[ For example\ NGF administration induces the rapid and persistent onset of both thermal and mechanical hyp! eralgesia in rodents[ In clinical trials\ patients have reported myalgia ð041Ð043Ł[ Both observations are in agreement with the _nding that NGF supports nocicep! tive sensory neurons ð04Ł[ The severity of de_ciencies in mice lacking speci_c neurotrophin functions suggests that activation of these signaling pathways is required in a wide variety of organs during ontogenesis[ Numerous experimental data\ sum! marized in this article\ that support such roles have been generated over the years[ Molecules are commonly named after the function for which they were discovered[ Many other factors\ not discussed here\ which originally were thought to function mainly in non!neuronal cell types\ also have neurotrophic activities\ although they are not structurally related to this neurotrophin family[ Conversely\ we will have to become more aware of the physiological activities of the {{so!called neurotrophins|| on non!neuronal cells[ A comprehensive analysis of the mutant mouse models should provide more de_nitive answers on the role of neurotrophins outside the nervous system[ One important limitation of the currently available mouse strains lacking neurotrophins or their receptors is their reduced life span\ precluding the analysis of neu! rotrophin functions in adulthood[ The development of new animal models with inducible targeted deletions will be necessary to allow the dissection of the full range of neurotrophin e}ects[ Lastly\ the integration of infor! mation from di}erent organ systems\ especially con! cerning their maturation and function\ should improve our knowledge of the possibilities and risks associated with manipulating neurotrophin signaling for therapeutic purposes[

Within the immune system\ neurotrophin receptors such as p64\ trkA and trkB are widely distributed ð15\ 16Ł and there is an increasing body of evidence indicating that NGF can regulate immune cell functions including in~ammatory responses "ð033Ł^ Table 1#[ For example\ NGF can promote colony growth and di}erentiation of myeloid precursors ð034Ł and can activate eosinophils ð094Ł\ monocytes ð093Ł and early!gene transcription in T cells ð035Ł[ However\ the most striking data concern the e}ects of NGF on mast cell ð098\ 001\ 003\ 034Ł and B! cell ð21\ 099Ð091Ł functions[ The physiological\ rather than pharmacological\ relevance of many of these e}ects\ observed mainly in vitro\ is not clear[ However\ recently\ some in vivo evidence has indicated a direct function of NGF on memory B!lymphocytes[ Torcia et al[ ð88Ł have reported that NGF is synthesized and released under basal conditions by normal human B!lymphocytes\ which also constitutively express both p64 and trkA receptors[ By neutralizing endogenous NGF\ they have shown that this neurotrophin functions in an autocrine fashion to maintain the viability of memory B!cells involved in sec! ondary humoral immune responses[ Clinical support for these experimental data can be found in human patho! logic conditions such as allergic ð036Ł and autoimmune ð037Ł diseases where there is a strong correlation between acute phases and NGF levels in either the bloodstream or in the in~ammation site[ Although the pathogenetic signi_cance of these data is not yet clear\ NGF is clearly an important element in the modulation of immune func! tions[ Currently\ there are insu.cient data in support of a similar role for the other neurotrophins "Table 1#[ The availability of mouse models lacking neurotrophins or their receptors should help clarify the role of NGF and the other neurotrophins in the immune system[ In the brain\ microglial cells are activated in response to injury\ infection and in~ammation of the nervous system[ It is known that microglia produces cytotoxic agents that induce neuron death and demyelination of oligodendrocytes ð038Ł[ However\ microglia is also a source of several growth factors\ including neur! otrophins\ suggesting a role in providing trophic support for neurons and glia ð038\ 049Ł[ Furthermore\ NT!2 pro! motes microglial proliferation and phagocytic activity\ suggesting that this factor plays a role in processes associ! ated with cellular activation ð040Ł[ These data suggest that neurotrophins play a role in the cross!talk between the immune system and neurons\ in addition to their well! known trophic e}ects on neurons[

Acknowled`ements] To my father Giuseppe "0821Ð0887#[ I am grateful to Esta Sterneck\ Pantelis Tsoulfas\ Enzo Coppola\ Eileen Southon\ Mary Ellen Palko and Ernest Lyons for sug! gestions and critical reading of the manuscript[ I also thank Madeline Wilson for help in preparing the manuscript and Anne Arthur for editing it[ L[ Tessarollo|s research is supported by the National Cancer Institute\ DHHS\ under contract with ABL[

PERSPECTIVES

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Analysis of genetically engineered mice lacking neu! rotrophins or their receptors has revealed some of the

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Pleiotropic Functions of Neurotrophins in Development 64[ Silos!Santiago I\ Fagan AM\ Garber M\ Fritzsh B\ Barbacid M[ Severe sensory de_cits but normal CNS development in newborn mice lacking TrkB and TrkC tyrosine protein kinase receptors[ Eur J Neurosci 0886\ 8\ 1934Ð1945[ 65[ Minichiello L\ Piehl F\ Vasquez E\ Schimmang T\ Hokfelt T\ Represa J\ Klein R[ Di}erential e}ects of combined trk receptor mutations on dorsal root ganglion and inner ear sensory neurons[ Development 0884\ 010\ 3956Ð3964[ 66[ Schimmang T\ Minichiello L\ Vazquez E\ San Jose I\ Giraldez F\ Klein R\ Represa J[ Developing inner ear sensory neurons require TrkB and TrkC receptors for innervation of their peripheral targets[ Development 0884\ 010\ 2270Ð2280[ 67[ Bianchi LM\ Conover JC\ Fritzsch B\ DeChiara T\ Lind! say RM\ Yancopoulos GD[ Degeneration of vestibular neurons in late embryogenesis of both heterozygous and homozygous BDNF null mutant mice[ Development 0885\ 011\ 0854Ð0862[ 68[ Ernfors P\ Van De Water T\ Loring J\ Jaenisch R[ Comp! lementary roles of BDNF and NT!2 in vestibular and auditory development[ Neuron 0884\ 03\ 0042Ð0053[ 79[ Erickson JT\ Conover JC\ Borday V\ Champagnat J\ Bar! bacid M\ Yancopoulos G\ Katz DM[ Mice lacking brain! derived neurotrophic factor exhibit visceral sensory neu! ron losses distinct from mice lacking NT3 and display a severe development de_cit in control of breathing[ J Neurosci 0885\ 05\ 4250Ð4260[ 70[ Crowley\ C\ Spencer SD\ Nishimura MC\ Chen KS\ Pitts! Meek S\ Armanini MP\ Ling LH\ McMahon SB\ Shelton DL\ Levinson AD\ Phillips HS[ Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons[ Cell 0883\ 65\ 0990Ð0900[ 71[ Fagan AM\ Zhang H\ Landis S\ Smeyne RJ\ Silos!San! tiago I\ Barbacid M[ TrkA\ but not trkC\ receptors are essential for survival of sympathetic neurons in vivo[ J[ Neurosci[ 0885\ 05\ 5197Ð5107[ 72[ Indo Y\ Tsuruta M\ Hayashida Y\ Karim MA\ Ohta K\ Kawano T\ Mitsubuchi H\ Tonoki H\ Awaya Y\ Matsuda I[ Mutations in the TRKA:NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis[ Nature Genet 0885\ 02\ 374Ð377[ 73[ Orioli D\ Klein R[ The Eph receptor family] axonal guid! ance by contact repulsion[ Trends Genet 0886\ 02\ 243Ð 248[ 74[ Mobley W\ Woo J\ Edwards R\ Riopelle R\ Longo F\ Weskamp G\ Otten U\ Valletta J\ Johnston M[ Devel! opmental regulation of nerve growth factor and its recep! tor in the rat caudate!putamen[ Neuron 0878\ 2\ 544Ð553[ 75[ Fagan AM\ Garber M\ Barbacid M\ Silos!Santiago I\ Holtzman DM[ A role for TrkA during maturation of striatal and basal forebrain cholinergic neurons in vivo[ J Neurosci 0886\ 06\ 6533Ð6543[ 76[ Alcantara S\ Frisen J\ del R(o JA\ Soriano E\ Barbacid M\ Silos!Santiago I[ TrkB signaling is required for postnatal survival of CNS neurons and protects hippocampal and motor neurons from axotomy!induced cell death[ J Neu! rosci 0886\ 06\ 2512Ð2522[ 77[ Kokaia Z\ Bengzon J\ Metsis M\ Kokaia M\ Persson H\ Lindvall O[ Coexpression of neurotrophins and their receptors in neurons of the central nervous system[ Proc Natl Acad Sci USA 0882\ 89\ 5600Ð5604[ 78[ Minichiello L\ Klein R[ TrkB and TrkC neurotrophin receptors co!operate in promoting survival of hip! pocampal and cerebellar granule neurons[ Genes + Dev 0885\ 09\ 1738Ð1747[ 89[ Schwartz PM\ Borghesani PR\ Levy RL\ Pomeroy SL\ Segal RA[ Abnormal cerebellar development and foliation in BDNF!:! mice reveals a role for neurotrophins in CNS patterning[ Neuron 0886\ 08\ 158Ð170[

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80[ Lindvall O\ Kokaia Z\ Bengzon J\ Elmer E\ Kokaia M[ Neurotrophins and brain insults[ TINS 0883[ 06\ 389Ð385[ 81[ Oppenheim RW[ Neurotrophic survival molecules for motoneurons] an embarrassment of riches[ Neuron 0885\ 06\ 084Ð086[ 82[ Tuszynski M\ Cage F[ Maintaining the neuronal pheno! type after injury in the adult CNS[ Neurotrophic factors\ axonal growth substrates\ and gene therapy[ Mol Neuro! biol 0884\ 09\ 040Ð056[ 83[ Lo DC[ Neurotrophic factors and synaptic plasticity[ Neu! ron 0884\ 04\ 868Ð870[ 84[ Thoenen H[ Neurotrophins and neuronal plasticity[ Sci! ence 0884\ 169\ 482Ð487[ 85[ Korte M\ Griesbeck O\ Gravel C\ Carroll P\ Staiger V\ Thoenen H\ Bonhoe}er T[ Virus!mediated gene transfer into hippocampal CA0 region restores long!term potent! iation in brain!derived neurotrophic factor mutant mice[ Proc Natl Acad Sci USA 0885\ 82\ 01436Ð01441[ 86[ Patterson SL\ Abel T\ Deuel TAS\ Martin KC\ Rose JC\ Kandel ER[ Recombinant BDNF rescues de_cits in basal synaptic transmission and hippocampus TP in BDNF knockout mice[ Neuron 0885\ 05\ 0026Ð0034[ 87[ Chen KS\ Nishimura MC\ Armanini MP\ Crowley C\ Spencer SD\ Phillips HS[ Disruption of a single allele of the nerve growth factor gene results in atrophy of basal forebrain cholinergic neurons and memory de_cits[ J Neu! rosci 0886\ 06\ 6177Ð6185[ 88[ Torcia M\ Bracci!Laudiero L\ Lucibello M\ Nencioni L\ Labardi D\ Rubartelli A\ Cozzolin F\ Aloe L\ Garaci E[ Nerve growth factor is an autocrine survival factor for memory B lymphocytes[ Cell 0885\ 74\ 234Ð245[ 099[ Brodie C\ Gelfand EW[ Functional nerve growth factor receptors on human B lymphocytes[ Interaction with IL! 1[ J Immunol 0881\ 037\ 2381Ð2386[ 090[ Brodie C\ Gelfand EW[ Regulation of immunoglobulin production by nerve growth factor] Comparison with anti! CD39[ J Neuroimmunol 0883\ 41\ 76Ð85[ 091[ Brodie C\ Oshiba A\ Renz H\ Bradley K\ Gelfand EW[ Nerve growth!factor and anti!CD39 provide opposite sig! nals for the production of IgE in interleukin!3!treated lymphocytes[ Eur J Immunol 0885\ 15\ 060Ð067[ 092[ Ehrhard PB\ Erb P\ Graumann U\ Schumtz B\ Otten U[ Expression of functional trk tyrosine kinase receptors after T cell activation[ J Immunol 0883\ 041\ 1694Ð1698[ 093[ Ehrhard PB\ Ganter U\ Bauer J\ Otten U[ Expression of functional trk proto!oncogene in human monocytes[ Proc Natl Acad Sci USA 0882\ 89\ 4312Ð4316[ 094[ Hamada A\ Watanabe N\ Ohtomo H[ Matsuda H\ Nerve growth factor enhances survival and cytotoxic activity of human eosinophils[ Brit J Haematol 0885\ 188Ð291[ 095[ Kannan Y\ Ushio H\ Koyama H\ Okada M\ Oikawa M\ Yoshihara T\ Kaneko M\ Matsuda H[ 1[4S nerve growth factor enhances survival\ phagocytosis\ and superoxide production of murine neutrophils[ Blood 0880\ 66\ 0219Ð 0214[ 096[ Matsuda H\ Switzer J\ Coughlin MD\ Bienenstock J\ Den! burg JA[ Human basophilic cell di}erentiation promoted by 1[4S nerve growth factor[ Int Arch Aller`y Appl Immu! nol 0877\ 75\ 342Ð346[ 097[ Boyle MDP\ Lawman MJP\ Gee AP\ Young M[ Nerve growth factor] A chemotactic factor for poly! morphonuclear leukocytes in vivo[ J Immunol 0874\ 023\ 453Ð457[ 098[ Tsuda T\ Wong D\ Dolovich J\ Bienenstock J\ Marshall J\ Denburg JA[ Synergistic e}ects of nerve growth factor and granulocyte!macrophage colony!stimulating factor on human basophilic cell di}erentiation[ Blood 0880\ 66\ 860Ð868[ 009[ Burgi B\ Otten UH\ Ochensberger B\ Rihs S\ Heese K\ Ehrhard PB\ Ibanez CF\ Dahinden CA[ Basophil priming

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L[ Tessarollo by neurotrophic factors] Activation through the trk recep! tor[ J Immunol 0885\ 046\ 4471Ð4477[ Bischo} SC\ Dahinden CA[ E}ect of nerve growth factor on the release of in~ammatory mediators by mature human basophils[ Blood 0881\ 68\ 1551Ð1558[ Horigome K\ Bullock ED\ Johnson JEM[ E}ects of nerve growth factor on rat peritoneal mast cells] Survival pro! motion and immediate early gene induction[ J Biol Chem 0883\ 158\ 1584Ð1691[ Kawamoto K\ Okada Y\ Kannan Y\ Ushio H\ Mat! sumoto M\ Matsuda H[ Nerve growth factor prevents apoptosis of rat peritoneal mast cells through the trk proto!oncogene receptor[ Blood 0884\ 75\ 3527Ð3533[ Matsuda H\ Kannan Y\ Ushio H\ Kiso Y\ Kanemoto T\ Suzuki H\ Kitamura Y[ Nerve growth factor induces development of connective tissue!type mast cells in vitro from murine bone marrow cells[ J Exp Med 0880\ 063\ 6Ð 03[ Horigome\ K\ Pryor JC\ Bullock ED\ Johnson EM[ Mediator release from mast cells by nerve growth factor] Neurotrophin speci_city and receptor mediation[ J Biol Chem 0882\ 157\ 03770Ð03776[ Marshall JS\ Stead RH\ McSharry C\ Nielsen L\ Bien! enstock J[ The role of mast cell degranulation products in mast cell hyperplasia[ I[ Mechanism of action of nerve growth factor[ J Immunol 0889\ 033\ 0775Ð0781[ Brodie C\ Sampson SR[ Nerve growth factor and _bro! blast growth factor in~uence post!fusion expression of Na!channels in cultured rat skeletal muscle[ J Cell Physiol 0889\ 033\ 381Ð386[ Donovan MJ\ Miranda RC\ Kraemer R\ McCa}rey TA\ Tessarollo L\ Mahadeo D\ Sharif S\ Kaplan DR\ Tsoulfas P\ Parada LF\ Toran!Allerand CD\ Hajjar DP\ Hempstead BL[ Neurotrophins and neurotrophin recep! tors in vascular smooth muscle cells] regulation of expression in response to injury[ Amer J Path 0884\ 036\ 298Ð213[ Di Marco E\ Mathor M\ Bondanza S\ Cutuli N\ Marchisio PC\ Cancedda R\ De Luca M\ Nerve growth factor binds to normal human keratinoctyes through high and low a.nity receptors and stimulates their growth by a novel autocrine loop[ J Biol Chem 0882\ 157\ 11727Ð11735[ Lillien LE\ Claude P[ Nerve growth factor is a mitogen for cultured chroma.n cells[ Nature 0874\ 206\ 521Ð523[ Yaar M\ Grossman K\ Eller M\ Gilchrest BA[ Evidence for nerve growth factor!mediated paracrine e}ects in human epidermis[ J Cell Biol 0880\ 004\ 710Ð717[ Hermann JL\ Menter DG\ Hamada J\ Marchetti D\ Naka! jima M\ Nicolson GL\ Mediation of NGF!stimulated extracellular matrix invasion by the human melanoma low!a.nity p64 neurotrophin receptor] melanoma p64 functions independently of trkA[ Mol Biol Cell 0882\ 3\ 0194Ð0105[ Yaar M\ Eller MS\ DiBenedetto P\ Reenstra WR\ Zhai S\ McQuaid T\ Archambault M\ Gilchrest BA[ The trk fam! ily of receptors mediates nerve growth factor and neu! rotrophin!2 e}ects in melanocytes[ J Clin Invest 0883\ 83\ 0449Ð0451[ Missale C\ Boroni F\ Sigala S\ Buriani A\ Fabris M\ Leon A\ Dal Toso R\ Spano P[ Nerve growth factor in the anterior pituitary] Localization in mammotroph cells and cosecretion with prolactin by a dopamine!regulated mech! anisms[ Proc Natl Acad Sci USA 0885\ 82\ 3139Ð3134[ Polak M\ Scharfmann R\ Seilheimer B\ Eisenbarth G\ Dressler D\ Verma IM\ Potter H[ Nerve growth factor induces neuron!like di}erentiation of an insulin!secreting pancreatic beta cell line[ Proc Natl Acad Sci USA 0882\ 89\ 4670Ð4674[ Scharfmann R\ Tazi A\ Polak M\ Kanaka C\ Czernichow P[ Expression of functional nerve growth factor receptors

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in pancreatic beta!cell lines and fetal rat islets in primary culture[ Diabetes 0882\ 31\ 0718Ð0725[ Mayerhofer A\ Dissen GA\ Parrott JA\ Hill DF\ May! erhofer D\ Gar_eld RE\ Costa ME\ Skinner MK\ Ojeda S R[ Involvement of nerve growth factor in the ovulatory cascade] trkA receptor activation inhibits gap junctional communication between thecal cells[ Endocrinolo`y 0885\ 026\ 4551Ð4569[ Waraksa JA\ Lindsay RM\ Ip NY\ Hutz RJ[ Neu! rotrophin!2 augments steriod secretion by hamster ovarian follicles in vitro[ Zoolo` Sci 0884\ 01\ 388Ð491[ Levi!Montalcini R[ The nerve growth factor 24 years later[ Science 0876\ 126\ 0043Ð0051[ Djakiew D\ P~ug B\ Dionne C\ Onoda M[ Postnatal expression of nerve growth factor receptors in the rat testis[ Biol Reprod 0883\ 40\ 103Ð110[ Dissen GA\ Hirsh_eld AN\ Malamed S\ Ojeda SR[ Expression of neurotrophins and their receptors in the mammalian ovary is developmentally regulated] changes at the time of folliculogenesis[ Endocrinolo`y 0884\ 025\ 3570Ð3581[ Dissen GA\ Hill DF\ Costa ME\ Les Dees CW\ Lara HE\ Ojeda SR[ A role for trkA nerve growth factor receptors in mammalian ovulation[ Endocrinolo`y 0885\ 026\ 087Ð 198[ Otten U\ Baumann JB\ Girard J[ Stimulation of the pitu! itary!adrenocortical axis by nerve growth factor[ Nature 0868\ 171\ 302Ð303[ Taglialatela G\ Angelucci L\ Scaccianoce S\ Foreman PJ\ Perez!Polo JR[ Nerve growth factor modulates the acti! vation of the hypothalamopituitary!adrenocortical axis during the stress response[ Endocrinolo`y 0880\ 018\ 1101Ð 1107[ Kononen J\ Soinila S\ Persson H\ Honkaniemi J\ Hokfelt T\ Pelto!Huikko M[ Neurotrophins and their receptors in the rat pituitary gland] regulation of BDNF and trkB mRNA levels by adrenal hormones[ Brain Res Mol Brain Res 0883\ 16\ 236Ð243[ Kononen J\ Hokfelt T\ Pelto!Huikko M[ E}ects of aging on the expression of neurotrophins and their receptors in the rat pituitary gland[ Neuroreport 0884\ 5\ 1318Ð1323[ Kanaka!Gantenbein C\ Dicou E\ Czernichow P\ Sch! arfmann R[ Presence of nerve growth factor and its recep! tors in an in vitro model of islet cell development implication in normal islet morphogenesis[ Endocrinolo`y 0884\ 025\ 2043Ð2051[ Shibayama E\ Koizumi H[ Cellular localization of the Trk neurotrophin receptor family in human non!neuronal tissues[ Am J Path 0885\ 037\ 0796Ð0707[ Tazi A\ Le Bras S\ Lamghitnia HW\ Vincent JD\ Czer! nichow P\ Scharfmann R[ Neurotrophin!2 increases intra! cellular calcium in a rat insulin!secreting cell line through its action on a functional TrkC receptor[ J Biol Chem 0885\ 160\ 09043Ð09059[ Tessarollo L\ Hempstead B[ Regulation of cardiac devel! opment by receptor tyrosine kinases[ Trends Cardiovasc Med 0887\ 7\ 21Ð27[ Scarisbrick IA\ Jones EG\ Isackson PJ\ Coexpression of mRNAs for NGF\ BDNF\ and NT!2 in the cardiovascular system of the pre! and postnatal rat[ J Neurosci 0882\ 02\ 764Ð782[ Donovan MJ\ Hahn R\ Tessarollo L\ Hempstead BL Identi_cation of an essential non!neuronal function of neurotrophin!2 in mammalian cardiac development[ Nat! ure Genet 0885\ 03\ 109Ð102[ Kalcheim C\ Barde Y!A\ Thoenen H\ Le Douarin NM[ In vivo e}ect of brain!derived neurotrophic factor on the survival of developing dorsal root ganglion cells[ EMBO J 0876\ 5\ 1760Ð1762[ Scully JL\ Otten U[ NGF] Not just for neurons[ Cell Biol Intl 0884\ 08\ 348Ð358[

Pleiotropic Functions of Neurotrophins in Development 034[ Matsuda H\ Coughlin MD\ Bienenstock J\ Denburg JA[ Nerve growth factor promotes human hemopoietic colony growth and di}erentiation[ Proc Natl Acad Sci USA 0877\ 74\ 5497Ð5401[ 035[ Ehrhard PB\ Otten U[ Postnatal ontogeny of the neuro! trophin receptors trk and trkB mRNA in rat sensory and sympathetic ganglia[ Neurosci Lett 0883\ 055\ 196Ð109[ 036[ Bonini S\ Lambiase A\ Bonini S\ Angelucci F\ Magrini L\ Manni L\ Aloe L[ Circulating nerve growth factor levels are increased in humans with allergic diseases and asthma[ Proc Natl Acad Sci USA 0885\ 82\ 09844Ð09859[ 037[ Aloe L\ Skaper SD\ Leon A\ Levi!Montalcini R[ Nerve growth factor and autoimmune diseases[ Autoimmunity 0883\ 08\ 030Ð049[ 038[ Giulian D\ Corpuz M[ Microglial secretion products and their impact on the nervous system[ Adv Neurol 0882\ 48\ 204Ð219[ 049[ Shimojo M\ Nakajima K\ Takei N\ Hamanoue M\ Kohsaka S[ Production of basic _broblast growth factor

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in cultured rat brain microglia[ Neurosci Lett 0880\ 012\ 118Ð120[ Elkabes S\ DiCicco!Bloom EM\ Black IB[ Brain mic! roglia:macrophages express neurotrophins that selectively regulate microglial proliferation and function[ J Neurosci 0885\ 05\ 1497Ð1410[ Zettler C\ Head RJ\ Rush RA\ Chronic nerve growth factor treatment of normotensive rats[ Brain Res 0880\ 427\ 140Ð151[ Petty BG\ Cornblath DR\ Adornato BT\ Chaudhry V\ Flexner C\ Wachsman M\ Sinicropi D\ Burton LE\ Per! outka SJ[ The e}ect of systemically administered recom! binant human nerve growth factor in healthy human subjects[ Ann Neurol 0883\ 25\ 133Ð135[ Apfel SC\ Adornato BT\ Cornblath DR[ An expanded phase I clinical trial of nerve growth factor in patients with peripheral neuropathy[ Neurolo`y 0884\ 34"supp 3#\ A167ÐA168[