Cholesterol homeotasis and hedgehogs

MONITOR. expression, fail to induce Nkx2.2 and promote the generation of interneurons. To elucidate the role of Pa:x:6 in the Pax6 controls progenitor cell identity and neuronal fate in response to graded SHH signalling production of SHH-dependent neuron.... Ericson, J. e/ al. Cel19Q, 1-20 the authors examined mice that lack functional PAx6 protein. In these mice, N1Ix2.2 expression is expanded dorprogenitors express the homeohox Specific classes of neurons are generated at disaete positions along the gene Nkx2.2 and give rise to ventral sally into progenitor cells that would dorsoventral axis of the vertebrate cen- motor neurons, whereas more dorsal nonnally express Pa:x:6 and there is a tral nervous system (CNS). In the ven- progenitors express the paiJ'ed-hox gene dorsal-to-ventral transformation of neurPQX6. and give rise to dorsal motor ons generated from this tenitory. These tral CNS, the secreted signalling protein Sonic hedgehog (SHH) is required for neurons and ventral interneuron.... The observations provide compelling evithe generation of motor neurons and authors show that high concentrations dence that graded SHH activity reguventral interneurons. Ericson et aI. of SHH In tJltmrepress Pa:x:6expression lates Pax6 expreRSion and that Pax6 demonstrate that graded SHH activity in progenitor cells, induce Nkx2.2 ex- activity (by preventing Nkx2.2 exinfluences the identity of these neur- pression and promote motor neuron pression) in progenitor cells influences production. By contrast, lower con- the identity of neurons generated in ons by regul~ting gene expression in 6 neuronal progenitors. Ventrally located centrations of SHH maintain Pa:x:6 ventral regions of the CNS.

Pax6 and neuronal fate

[-lox - r.egulation an.d fun.ction. Co-Jocalization of Polycomb protein and GAGA fador on regulatory elements responsible for the maintenance of homeotic gene expres.~ion . Strutt, H., CaVllIli, G. and Paro, R. EMBOJ. 16, 3621-3632 Functional dissection of a transcriptionally active, target-specific Hox-Pbx complex Di Rocco, G., Mavilio. F. and lappavigna. V. EMBO}. 16, 3644-3654 Our extensive knowledge of the conservation of Hox genes throughout the animal kingdom makes a striking contrast with our relative lack d knowledge about h()w they are regulated and how they function. In DrosopbtIa, regulation of Hox genes involves the Polycomh group (PcG) and the trltborax group ( 1rxG) genes; they are thought to stabilize expression states of the Hox genes by binding to broad regions within the cluster. Strutt et al. show that only a few elements within the complex show a IItTOng POLYCOMB protein binding. Thec;e elements coincide largely with

previously identified PcG re:.'POnse elements (PRE). However, the results also suggest. that POLYCOMB pn>teins spread fn>m these PREs over several kb. Jnterestingly, they also find a GAGA factor binding to the same sites. GAGA factor binding has so far been found in promotor regions, but not in distant enhancers. However, GAGA factor bek)ll~ to the TRXG group in Drosophila. In this respect it seems fitting that the products of the two groups eX genes that are involved in sllendng or activating et'fe<.1s should bind to the same primary sequence elements. The details of

Cholesterol homeostasis and. Iledgehogs Niemann-Pick Cl dilieaBe gene: homology to mediators of cholesterol homeoslaliill Carstea, E.D. el al. Science 277. 228-23] . Murine model of Niemann-Pick C disease: mutation in a choleliterol homeostasis gene J..oftu.~. S.Z. el al. Science 277. 232-235 Mutations in genes involved in cOOIesternl homeostasis can cause severe metabolic and degenerative disorders. Ever since the pioneering work of Brown and Goldstein in familial hyperchulesterolemia and the idenUfication of the ]n], l'<."CCptor, the study of rare dise-d8eS affecting cholesrernl metaholi!>'1n has clarified our view of dx)lesrerol hOIll<.'f>Stasis. The 1llC).')1 recent insigllts come from Niemann-Pick C (NP-C) syndrome, a nare but fatal disease caulled by a severe neurodegeneration. NP-C mutant cells fall to distribute cholesterol

properly within intracellular compartments: cholesterol accumulates in Iysosomes and this underlies the degenerative proces.... Carstea et. al. now report the isolation and characterization of mutations in the gene responsihle for NP-C (NPCI). Moreover, the parallel characterization of the mouse NpcJ ortholog O)y Loftus et al.) will accelerate the biochemical analysis of the protein product. The human and mouse NPC1 proteins share five stretches of se
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their interactions at these sites remain a matter of speculation. Di Rocco eI al. examine Ho:1C function, in particular how Hox genes achieve d1eir regulatory specificity, when most Hoxgenes bind in Vitro to the same consensus binding site. There is good evidence that interaction with other highly conserved homeodomain proteins, the PBX/EXD family, can increase the specificity of binding. Di Rocco et al test this model using a well-defined natural Hoxtarget. the mouo;e HClXhl autoregulatory element. They show that HOXB1 activates this element only in conjunction with PBXl. Hox genes of paralogy groups 1 and 2 activate this element with PBX1, but none of the other Hoxgenes tested. These results strengthen the !>ignificance of the interaction between the HOX and PBXIEXD proteins for generating the specificity of Hox gene action. although it still ~.. necessary that other factor'S mu'it playa role, to explain the whole range of specificities. ~

and one of them seems to be a ~1erol­ sensing domain (SSD). This SSJ) walt first discovered in HMG-CoA reductase .(the key regulatory enzyme in choleRterol biosynthesis) and later predicted to be present in SCAP, another protein involved in cholesterol homeostasis. The SSD, comprising five potential hydrophobic a-helices, has also been detec.11.'tJ in Patched (PTe) proteins. And here there arises a message for developmental hiolOWtits: PTe acts as a H<.~ge­ hog QiR) receptor and the IiH f-amily of Signaling ligands work with a cholesterol molecule covalently attached to the C-termlnal amino acid. So the molecular analysis of NP-C has opened the way for the :1AAeS.'iIllerlt of novel pharmacological therapies for this disease, but has also led to an unexpected view of how lYJ'C receptors might decode dle HH signal in development. ~