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Regulation of neural precursor survival, proliferation and differentiation by BDNF
Symposia & Short Talk Abstracts / Int. J. Devl Neuroscience 24 (2006) 471–493
the UNC-5 pathway to mediate axon guidance, Data supporting this role will be presented.
doi:10.1016/j.ijdevneu.2006.09.051 Growth factors and cell fate decisions [S43] Development of the dentate neurogenic niche S. Pleasure University of California San Francisco, USA The dentate gyrus is one of the two locations in the adult rodent brain with ongoing neurogenesis. The ability to produce new neurons in the dentate is dependent on the relocation of neurogenic stem cells from the dentate ventricular zone to the hilus and later the subgranular zone during late prenatal and early postnatal development. There is abundant emphasis on the components of the adult neurogenic niche in the dentate but little is known of the processes controlling development of this niche. In this talk I will describe a conceptual framework for understanding the development of the dentate neurogenic niche, some of the key developmental regulatory events and discuss data showing that the chemokine SDF1 is a key regulator shaping the development of the dentate neurogenic niche. doi:10.1016/j.ijdevneu.2006.09.052 [S44] Regulation of neural precursor survival, proliferation and differentiation by BDNF P.F. Bartlett a, K. Young a, N. Bull, D. Jhaveri University of Queensland, Australia Present address: University College London UK.
a
It is now becoming increasingly clear from studies where neurogenesis is modulated by behavioural or pharmacological factors that BDNF levels may be one of the key regulating factors. In exploring the receptor repertoire expressed by a purified population of precursors isolated for the mouse SVZ, we found that a receptor for BDNF, the p75 neurotrophin receptor (NTR), was expressed. Using anti-p75NTR antibodies we were able to isolate a population expressing this receptor from the SVZ of the adult and neonatal rat. In vitro studies revealed that P75NTR +ve cells were highly enriched for precursors as assessed by the neurosphere assay with between 50 and 80% of the sorted cells giving rise to neurospheres. It was also found that neuronal production was predominantly found in the spheres derived from P75NTR
491
+ve cells and was dependent on the addition of high levels of BDNF, but not other neurtrophins. More recent work has shown that BDNF, but not other neurtrophins, is able to directly stimulate the survival and proliferation of neurosphere-forming precursors without the addition of either FGF or EGF. BDNF-stimulated spheres are small and are predominantly comprised of neurons, however, when re-stimulated with EGF or FGF they form large neurospheres containing all neural cell types. Similar, actions of BDNF are found on hippocampal precursors. Thus, BDNF appears to have multiple functions in regulating neuronal production, from stimulating the proliferation and survival of neuronal progenitors through to promoting neuronal differentiation. These various actions may explain the potency of BDNF as a neuronal regulator in a number of neurogenic regions. doi:10.1016/j.ijdevneu.2006.09.053 [ST7] An activated SHP-2 mutant that causes noonan syndrome and is associated with cognitive impairments pertubs cell fates of cerebral cortex precursors A. Gauthier 1,2,*, T. Araki 3, B. Neel 3, D.R. Kaplan 1,2, F.D. Miller 1,2 1
University of Toronto, Canada; 2 Hospital for Sick Children, Canada; 3 Beth Israel Deaconess Medical Center, USA Pertubations in cell fate decisions during early cerebral cortex development have yet to be associated with cognitive impairments observed in human disorders. Noonan syndrome (NS) is a genetic disorder in which up to fifty percent of patients present with learning disabilities or mental retardation. Since fifty percent of NS cases are caused by activating SHP-2 mutations, we studied the role of these protein tyrosine phosphates in early neural development. During cerebral cortex development, precursor cells in the ventricular zone differentiate into neurons, astrocytes and oligodendrocytes in a temporally regulated manner based upon exposure to neurogenic and gliogenic signals. As SHP-2 can regulate MAP kinase activation, a signaling pathway important for neurogenesis, and inhibit gliogenic pathways such as JAK/ STAT, we hypothesized that the hyperactivation of SHP-2 that occurs in NS perturbs the balance between neurons and glia during development. Using a primary murine cortical precursor culture system, we found that inhibiting endogenous SHP-2 suppresses neurogenesis and enhances gliogenesis in response to the cytokine CNTF, while increasing SHP-2 activity with a NS-associated activated mutant promotes neurogenesis and suppresses gliogenesis. In utero electroporation of E13–14 cerebral cortex precursors demonstrated the same phenomena in vivo, inhibition of SHP-2 activity suppressed the generation of neurons and increased the generation of astrocytes, while a NS-associated activated
the UNC-5 pathway to mediate axon guidance, Data supporting this role will be presented.
doi:10.1016/j.ijdevneu.2006.09.051 Growth factors and cell fate decisions [S43] Development of the dentate neurogenic niche S. Pleasure University of California San Francisco, USA The dentate gyrus is one of the two locations in the adult rodent brain with ongoing neurogenesis. The ability to produce new neurons in the dentate is dependent on the relocation of neurogenic stem cells from the dentate ventricular zone to the hilus and later the subgranular zone during late prenatal and early postnatal development. There is abundant emphasis on the components of the adult neurogenic niche in the dentate but little is known of the processes controlling development of this niche. In this talk I will describe a conceptual framework for understanding the development of the dentate neurogenic niche, some of the key developmental regulatory events and discuss data showing that the chemokine SDF1 is a key regulator shaping the development of the dentate neurogenic niche. doi:10.1016/j.ijdevneu.2006.09.052 [S44] Regulation of neural precursor survival, proliferation and differentiation by BDNF P.F. Bartlett a, K. Young a, N. Bull, D. Jhaveri University of Queensland, Australia Present address: University College London UK.
a
It is now becoming increasingly clear from studies where neurogenesis is modulated by behavioural or pharmacological factors that BDNF levels may be one of the key regulating factors. In exploring the receptor repertoire expressed by a purified population of precursors isolated for the mouse SVZ, we found that a receptor for BDNF, the p75 neurotrophin receptor (NTR), was expressed. Using anti-p75NTR antibodies we were able to isolate a population expressing this receptor from the SVZ of the adult and neonatal rat. In vitro studies revealed that P75NTR +ve cells were highly enriched for precursors as assessed by the neurosphere assay with between 50 and 80% of the sorted cells giving rise to neurospheres. It was also found that neuronal production was predominantly found in the spheres derived from P75NTR
491
+ve cells and was dependent on the addition of high levels of BDNF, but not other neurtrophins. More recent work has shown that BDNF, but not other neurtrophins, is able to directly stimulate the survival and proliferation of neurosphere-forming precursors without the addition of either FGF or EGF. BDNF-stimulated spheres are small and are predominantly comprised of neurons, however, when re-stimulated with EGF or FGF they form large neurospheres containing all neural cell types. Similar, actions of BDNF are found on hippocampal precursors. Thus, BDNF appears to have multiple functions in regulating neuronal production, from stimulating the proliferation and survival of neuronal progenitors through to promoting neuronal differentiation. These various actions may explain the potency of BDNF as a neuronal regulator in a number of neurogenic regions. doi:10.1016/j.ijdevneu.2006.09.053 [ST7] An activated SHP-2 mutant that causes noonan syndrome and is associated with cognitive impairments pertubs cell fates of cerebral cortex precursors A. Gauthier 1,2,*, T. Araki 3, B. Neel 3, D.R. Kaplan 1,2, F.D. Miller 1,2 1
University of Toronto, Canada; 2 Hospital for Sick Children, Canada; 3 Beth Israel Deaconess Medical Center, USA Pertubations in cell fate decisions during early cerebral cortex development have yet to be associated with cognitive impairments observed in human disorders. Noonan syndrome (NS) is a genetic disorder in which up to fifty percent of patients present with learning disabilities or mental retardation. Since fifty percent of NS cases are caused by activating SHP-2 mutations, we studied the role of these protein tyrosine phosphates in early neural development. During cerebral cortex development, precursor cells in the ventricular zone differentiate into neurons, astrocytes and oligodendrocytes in a temporally regulated manner based upon exposure to neurogenic and gliogenic signals. As SHP-2 can regulate MAP kinase activation, a signaling pathway important for neurogenesis, and inhibit gliogenic pathways such as JAK/ STAT, we hypothesized that the hyperactivation of SHP-2 that occurs in NS perturbs the balance between neurons and glia during development. Using a primary murine cortical precursor culture system, we found that inhibiting endogenous SHP-2 suppresses neurogenesis and enhances gliogenesis in response to the cytokine CNTF, while increasing SHP-2 activity with a NS-associated activated mutant promotes neurogenesis and suppresses gliogenesis. In utero electroporation of E13–14 cerebral cortex precursors demonstrated the same phenomena in vivo, inhibition of SHP-2 activity suppressed the generation of neurons and increased the generation of astrocytes, while a NS-associated activated