Specifying motor neurons_mini review

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Unformatted text preview: © 2003 Nature Publishing Group http://www.nature.com/natureneuroscience NEWS AND VIEWS better incorporate the findings that have recently revised our concept of radial glial cells13–15. Only live observations—preferably in vivo—will enable researchers to piece together into a coherent model the data on different modes of neurogenesis and how these impinge on the way that neurons migrate. With such knowledge, we may also be better equipped to understand and eventually treat neuronal migration disorders. 1. Ross, E.M. & Walsh, C. Annu. Rev. Neurosci. 24, 1041–1070 (2001). 2. Gleeson, J.G. et al. Cell 92, 63–72 (1998). 3. Corbo, J.C. et al. J. Neurosci. 22, 7548–7557 (2002). 4. Bai, J. et al. Nat. Neurosci. 6, 1277–1283 (2003). 5. Behrends, A. & Aguzzi, A. Trends Neurosci. 25, 150–154 (2002). 6. Olson, E.N., Arnold, H.-H., Rigby, P.W.J. & Wold, B.J. Cell 85, 1–4 (1996). 7. Francis, F. et al. Neuron 23, 247–256 (1999). 8. Gleeson, J.G., Lin, P.T., Flanagan, L.A. & Walsh, C. Neuron 23, 257–271 (1999). 9. Dykxhoorn, D.M., Novina, C.D. & Sharpe, P.A. Nat. Rev. Mol. Cell Biol. 4, 457–467 (2003). 10. Frantz, S. N at. Rev. Drug Dis. 2 , 763–764 (2003). 11. Marin, O. & Rubenstein, J.L. Annu. Rev. Neurosci. 26, 441–483 (2003). 12. Miyata, T., Kawaguchi, A., Okano, H. & Ogawa, M. Neuron 31, 727–741 (2001). 13. Morest, D.K. & Silver, J. Glia 43, 6–18 (2003). 14. Malatesta, P. et al. Neuron 37, 751–764 (2003). 15. Gupta, A. et al. Nat. Neurosci. 6, 1284–1291 (2003). Specifying motor neurons: up and down and back to front William A Harris A recent study in Nature shows that the columnar fate of motor neurons in the embryonic spinal cord is imposed by crossrepressive patterns of Hox-c expression. This Hox expression is in turn controlled by graded FGF signaling. During development, motor neurons are organized along the head-to-tail or rostralcaudal axis of the spinal cord into distinct columns, which innervate different targets1. The cervical cord, for example, has a lateral motor column (LMC) that innervates the forelimb, whereas the thoracic cord has a distinct set of autonomic motor neurons in the Column of Terni (CT). Because the spinal motor neurons come from progenitor cells in the same ventral region of the neural tube, the columnar organization is thought to come from an independent rostral-caudal patterning mechanism. In a stunning study in Nature, Dasen, Liu and Jessell2 now show that the rostral-caudal patterning of motor neurons into columns occurs in response to a gradient of fibroblast growth factor (FGF). This gradient establishes domains of a family of homeobox (Hox) genes, which are expressed at different levels; the boundaries between these domains then establish the boundaries of the different motor pools. To appreciate how FGF signaling could be working to establish motor columns, it helps to think about how the spinal cord develops in the embryo. During gastrulation, cells involute through the primitive streak, a strip of cells that defines the rostral-caudal axis of the embryo. The site of involution is called the node, and as gastrulation proceeds, the William Harris is at the Department of Anatomy, Cambridge University, Downing Street, Cambridge CB2 3DY, UK. e-mail: harris@mole.bio.cam.ac.uk node regresses caudally along the streak, leaving more mature involuted mesodermal cells more rostrally. Near the node is the presomitic mesoderm, which expresses FGF8, and which now directly underlies the forming neural plate3. Two recent papers in Neuron show that FGF inhibits neuronal differentiation at this stage, and so the cells in the overlying neural plate remain as dividing neuroepithelial cells3,4. Previous transplant studies in chicks show that the transposition of mesoderm from thoracic to cervical levels changes the fate of the overlying motor neuron columns from LMC to CT identities5. Moreover, previous studies6,7 show that caudal mesoderm expresses higher levels of FGF8 than does rostral mesoderm, and that the low levels of FGF induce the expression of rostral Hox genes such as Hoxc5 and Hoxc6, whereas high levels of FGF induce the expression of the more caudal genes Hoxc8 and Hoxc9. Thus, FGF8 released from the presomitic mesoderm, although it keeps motor neurons from differentiating, also seems to be involved in patterning the rostral-caudal axis of the spinal cord. The simple hypothesis is that FGF8 regulates the pattern of Hox genes, which in turn specify motor column identity. Dasen et al.2 now provide direct evidence in support of this hypothesis, by reporting that the progenitor cells that give rise to motor neurons express Hox proteins in response to graded FGF signaling, and that motor neuron columnar fate develops through the transcriptional functions of the Hox proteins. In embryonic chick spinal cord, they found that Hox protein expression N ATURE NEUROSCIENCE VOLUME 6 | NUMBER 12 | DECEMBER 2003 segregated with motor neuron columnar subtype. For instance, Hoxc6 expression was confined to cervical levels of the embryonic spinal cord, whereas Hoxc9 expression was restricted to thoracic levels. When FGF8 signaling was increased in the neural tube, this caused a repression of Hoxc6 expression and the onset of Hoxc9 expression at cervical levels. Moreover, if Hoxc9 was misexpressed cervically, it repressed the expression of Hoxc6, and when Hoxc6 was misexpressed thoracically, it repressed the expression of Hoxc9, showing that there is mutual inhibition, leading to a sharp border between Hoxc6and Hoxc9-expressing motor neurons. No neurons expressed both Hoxc6 and Hoxc9. Similar mutual repression was found between Hoxc5 and Hoxc8. Hoxc6-expressing motor neurons, whether they were in the normal cervical position or the abnormal thoracic position, showed characteristics of the LMC, such as expression of the retinoic acid synthesizing enzyme Raldh2, axonal projections toward the limb bud, and an ovoid cross-section in the cord. Similarly, Hoxc9-expressing neurons, whether they were in their normal thoracic position or in the cervical region (due to treatment with extra FGF or misexpression), showed CT characteristics such as BMP5 expression, axonal projection to the sympathetic chain and a medial semi-lunar cross-section in the cord. Thus an FGF gradient establishes a motor neuron Hox pattern that determines columnar phenotype. Developmental neurobiologists will appreciate that this logic is strikingly similar to that governing the positioning of the motor neu- 1247 © 2003 Nature Publishing Group http://www.nature.com/natureneuroscience NEWS AND VIEWS Figure 1 Motor neuron specification in the dorsoventral and rostrocaudal axis of the spinal cord. The spinal cord diagram (b) shows the ventral location of the motor neurons and two different motor columns that arise at different rostrocaudal levels of the cord. Ventral to the cord is the medial notochord, and the paraxial mesoderm. (a) A gradient of Shh emanates from the notochord and floor plate; threshold levels of Shh turn on Class-II HD genes. Retinoic acid (RA) expressed by the paraxial mesoderm induces the expression of Class-I HD genes that are turned off more ventrally by threshold levels of Shh. Class-I and Class-II HD transcription factors cross repress each other, creating sharp definitive boundaries at different dorsoventral levels in the cord. Thus the boundary between Dbx and Nkx6 is more dorsal than the boundary between Pax6 and Nkx2.2. Between these boundaries, the OLIG2 bHLH transcription factor necessary for motor neuron specification is turned on by the concerted action of RA, Nkx6 and Pax6. OLIG2 and RA are necessary for the expression of motor neuron identity genes in motor neuron precursors (pMN). (c) A gradient of FGF8 emanates from the mesoderm. High levels of FGF8 turn on more caudal Hoxc genes, whereas RA and low levels of FGF8 turn on rostral Hoxc genes. Rostral and caudal Hoxc transcription factors cross-repress each other, creating sharp definitive boundaries at different rostrocaudal levels in the cord. The boundary between Hoxc6 and Hoxc9 establishes the boundary between the LMC of the cervical cord and the CT of the thoracic cord. The significance of the Hoxc5 and Hoxc8 boundary is unknown. rons in the ventral region of the spinal cord, which the Jessell laboratory has demonstrated in a series of exceptional papers (reviewed in ref. 8). Dorsal-ventral patterning in the spinal cord begins in response to a gradient of Sonic hedgehog (Shh) protein secreted by the notochord and then the floor plate. This gradient sets up expression domains of two kinds of homeodomain (HD) transcription factors: Class-I HD factors (like Nkx2.2 and Nkx), which are turned on in the ventral cord by high levels of Shh, and the more dorsal Class-II HD factors (Pax6 and Dbx2), which are turned off by high levels of Shh in the ventral cord. Class-I and Class-II HD genes are differentially sensitive to Shh and form cross-inhibitory relationships such that sharp borders of expression are set up at different dorsoventral levels of the spinal cord. These borders define discrete dorsal-ventral domains of the cord, including the domain of motor neurons. The domain that expresses both the Class-I HD gene Nkx6 and the Class-II HD gene Pax6 also turns on OLIG2, a bHLH transcription factor that is required for motor neuron differentiation. OLIG2 cells then turn on motor neuron identity genes such as Mnx and Lim3, initiating the program of motor neuron differentiation in this domain (Fig. 1). Novitch et al.3 and Diez et al.4 show that in addition to Shh, FGF8 and retinoic acid (RA) are also involved in the dorsal-ventral patterning of the spinal cord3,4, and RA contributes to establishing the rostral-caudal pattern of motor columns9. Thus, FGF8 and RA are 1248 involved in both the rostral-caudal and dorsalventral specification of motor neurons. To understand how this works, let us return to the developing embryo. At mid-gastrulation, the node has proceeded half way down the primitive streak, creating a rostral-to-caudal gradient of differentiation. Rostrally, the mesoderm that involuted through the node earlier has organized itself into a ventromedial notocord and a lateral somitic or paraxial mesoderm. At this stage, FGF8 is turned off in the mesoderm, which allows the differentiation of motor neurons in the overlying neural plate, now curling itself into a neural tube that will form the spinal cord3,4. At this time also, the paraxial mesoderm begins secreting RA, while the notochord begins secreting Shh3. RA inhibits FGF8 expression in the somitic mesoderm. Similarly FGF turns off RA expression4. This reinforces a pattern in which posterior somatic mesoderm is higher in FGF signaling while more anterior presomitic mesoderm is higher in RA. In the anterior region, high RA collaborates with low FGF in turning on the neural differentiation program4. Sockonathan et al.9 now show that RA also collaborates with FGF in columnar specification. Cervical motor neurons expressing dominant-negative RA receptors acquire the phenotypes of CT motor neurons, whereas expression of constitutively active RA receptors in thoracic regions prevents the normal differentiation of CT motor neurons9. How do these signaling systems contribute to the transcriptional cascade involved in the dorsal-ventral positioning of motor neurons? By exploring how FGF inhibits motor neuron differentiation, it was discovered that FGF signaling inhibits the expression of both ventral Class-I and dorsal Class-II HD transcription factors in the neural tube3,4. Shh, as we know, is expressed by the notochord as FGF signaling is turned off, and turns on the ventral Class-II HD genes8. But how do the Class-II HD genes get turned on? RA is expressed more dorsally by the paraxial mesoderm and can activate Class-II HD genes3. Thus, the combination of RA and Shh signaling turns on both the Class-I and ClassII HD gene. Interestingly, most of the transcription factors in the dorsal-ventral cascade work as repressors. For example, Nkx6 and Pax6 do not directly induce OLIG2, OLIG2 as a repressor cannot directly induce motor neuron identity genes. In both of these steps, RA signaling is required, as dominant-negative RA receptors misexpressed at either stage block progression of the cells toward the motor neuron fate. RA might therefore act as a de-repressive signaling system needed to inhibit the repressors in this essentially repressive transcriptional network3. This new work leaves us with a much richer view of how the three-dimensional system of motor neurons develops in an animal by the coordinated time-dependent, concentration-dependent and positiondependent actions of FGF, RA and Shh. That FGF8 and RA are involved in both dorsalventral and rostral-caudal patterning may VOLUME 6 | NUMBER 12 | DECEMBER 2003 N ATURE NEUROSCIENCE © 2003 Nature Publishing Group http://www.nature.com/natureneuroscience NEWS AND VIEWS only be possible because they are working during embryogenesis, a kind of timewarped space where the relative position of signaling centers and responding cells change as a function of developmental time. These findings strongly resemble limb morphogenesis, in which a complex timedependent integration of BMP, RA, Shh and FGF signaling within rostral-caudal, dorsalventral and proximal-distal axes create distinct Hox protein patterns that specify bone and digit identity. The new data also raise intriguing new questions such as how exactly RA-mediated de-repression works. The dissociation of CT and LMC columns is only the beginning of a dissection of several different motor columns and subdivisions of motor columns that have overlapping yet distinct locations along the extent of the spinal cord. Still, the recent work has added a new dimension to the work on motor neuron development, by showing that the principles of homeodomain protein function along the dorsalventral axis and rostral-caudal axis are similar—a graded activity of a signaling factor establishes homeodomain boundaries, which are further refined by selective crossrepression among the homeodomain transcription factors. The convergence of these two programs then ensures correct motor neuron specification along the dorsal-ventral and rostral-caudal axes. 1. Tosney, K.W., Hotary, K.B. & Lance-Jones, C. Bioessays 17, 379–382 (1995). 2. Dasen, J., Liu, J.-P. & Jessell, T. Nature 425, 926–933 (2003). 3. Novitch, B.G., Wichterle, H., Jessell, T.M. & Sockanathan, S. Neuron 40, 81–95 (2003). 4. Diez del Corral, R. et al. Neuron 40, 65–79 (2003). 5. Ensini, M., Tsuchida, T.N., Belting, H.G. & Jessell, T.M. Development 125, 969–982 (1998). 6. Liu, J.P., Laufer, E. & Jessell, T.M. Neuron 32, 997–1012 (2001). 7. Bel-Vialar, S., Itasaki, N. & Krumlauf, R. Development 129, 5103–5115 (2002). 8. Jessell, T. M. Nat. Rev. Genet. 1, 20–29 (2000). 9. Sockanathan, S., Perlmann, T. & Jessell, T.M. Neuron 40, 97–111 (2003). Folding the cortex The cortical surface of a normal mouse is smooth (top). The cortices of primates, including humans, are folded up into a complex landscape of gyri and sulci. In this issue (page 1292), Kingsbury et al. report that treating cultured cortical hemispheres from mouse embryos with lysophosphatidic acid (LPA) for only 17 hours caused them to expand and fold up into a structure that resembles a primate brain (bottom; blue is DAPI staining). The folded cortices were thicker and contained more cells than controls: both more differentiated neurons in the cortical plate and more neural progenitor cells in the ventricular zone. LPA induced terminal mitosis—the generation of neurons from progenitors—and it also reduced apoptotic death of progenitor cells. Although LPA can induce cell proliferation in other systems, Kingsbury et al. saw no increase in S-phase cells, so most of the increase in cell number seemed to be due to inhibition of cell death. The effects of LPA were mediated by one or both of the closely related G protein–coupled receptors LPA1 and LPA2, as cortices from mouse embryos lacking these two receptors did not fold up after LPA treatment. Neurons in the brain produce LPA, which can activate a number of intracellular signaling pathways. Despite the presence of the LPA signal, however, mice lacking LPA1, LPA2 or both receptors show no evident cortex malformation, suggesting that such signals are not important for the development of the smooth cortex of the mouse. On the other hand, the ability of excess LPA to induce cortical folding in mice suggests the intriguing possibility that LPA might contribute to cortical development in primates. Annette Markus NATURE NEUROSCIENCE VOLUME 6 | NUMBER 12 | DECEMBER 2003 1249 ...
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