Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Motor neuron columnar fate imposed by sequential phases of Hox-c activity

Abstract

The organization of neurons into columns is a prominent feature of central nervous system structure and function. In many regions of the central nervous system the grouping of neurons into columns links cell-body position to axonal trajectory, thus contributing to the establishment of topographic neural maps. This link is prominent in the developing spinal cord, where columnar sets of motor neurons innervate distinct targets in the periphery. We show here that sequential phases of Hox-c protein expression and activity control the columnar differentiation of spinal motor neurons. Hox expression in neural progenitors is established by graded fibroblast growth factor signalling and translated into a distinct motor neuron Hox pattern. Motor neuron columnar fate then emerges through cell autonomous repressor and activator functions of Hox proteins. Hox proteins also direct the expression of genes that establish motor topographic projections, thus implicating Hox proteins as critical determinants of spinal motor neuron identity and organization.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Hox-c protein expression and spinal motor neuron columnar identity.
Figure 2: Hox-c and motor column repatterning after FGF8 expression in brachial neural tube.
Figure 3: Motor columnar patterning activities of Hoxc9 and Hoxc6.
Figure 4: Rapid repatterning of neural progenitor Hox profile after brachial FGF8 expression.
Figure 5: Activities of Hoxc6 and Hoxc9 in post-mitotic neurons.
Figure 6: Actions of Engrailed repressor derivatives of Hoxc6 and Hoxc9 on columnar differentiation.
Figure 7: Hox6 and Hox9 activities in motor neuron columnar differentiation and topography.

References

  1. Mountcastle, V. B. The columnar organization of the neocortex. Brain 120, 701–722 (1997)

    Article  PubMed  Google Scholar 

  2. Sanders, T. A., Lumsden, A. & Ragsdale, C. W. Arcuate plan of chick midbrain development. J. Neurosci. 22, 10742–10750 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Jessell, T. M. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nature Rev. Genet. 1, 20–29 (2000)

    CAS  PubMed  Google Scholar 

  4. Briscoe, J. & Ericson, J. Specification of neuronal fates in the ventral neural tube. Curr. Opin. Neurobiol. 11, 43–49 (2001)

    Article  CAS  PubMed  Google Scholar 

  5. Landmesser, L. The distribution of motoneurones supplying chick hind limb muscles. J. Physiol. (Lond.) 284, 371–389 (1978)

    Article  CAS  Google Scholar 

  6. Hollyday, M. Organization of motor pools in the chick lumbar lateral motor column. J. Comp. Neurol. 194, 143–170 (1980)

    Article  CAS  PubMed  Google Scholar 

  7. Hollyday, M. Motoneuron histogenesis and the development of limb innervation. Curr. Top. Dev. Biol. 15, 181–215 (1980)

    Article  PubMed  Google Scholar 

  8. Gutman, C. R., Ajmera, M. K. & Hollyday, M. Organization of motor pools supplying axial muscles in the chicken. Brain Res. 609, 129–136 (1993)

    Article  CAS  PubMed  Google Scholar 

  9. Shirasaki, R. & Pfaff, S. L. Transcriptional codes and the control of neuronal identity. Annu. Rev. Neurosci. 25, 251–281 (2002)

    Article  CAS  PubMed  Google Scholar 

  10. Ensini, M., Tsuchida, T. N., Belting, H. G. & Jessell, T. M. The control of rostrocaudal pattern in the developing spinal cord: specification of motor neuron subtype identity is initiated by signals from paraxial mesoderm. Development 125, 969–982 (1998)

    CAS  PubMed  Google Scholar 

  11. Liu, J. P., Laufer, E. & Jessell, T. M. Assigning the positional identity of spinal motor neurons: rostrocaudal patterning of Hox-c expression by FGFs, Gdf11, and retinoids. Neuron 32, 997–1012 (2001)

    Article  CAS  PubMed  Google Scholar 

  12. Bel-Vialar, S., Itasaki, N. & Krumlauf, R. Initiating Hox gene expression: in the early chick neural tube differential sensitivity to FGF and RA signaling subdivides the HoxB genes in two distinct groups. Development 129, 5103–5115 (2002)

    CAS  PubMed  Google Scholar 

  13. Studer, M., Lumsden, A., Ariza-McNaughton, L., Bradley, A. & Krumlauf, R. Altered segmental identity and abnormal migration of motor neurons in mice lacking Hoxb-1. Nature 384, 630–634 (1996)

    Article  ADS  CAS  PubMed  Google Scholar 

  14. Bell, E., Wingate, R. J. & Lumsden, A. Homeotic transformation of rhombomere identity after localized Hoxb1 misexpression. Science 284, 2168–2171 (1999)

    Article  CAS  PubMed  Google Scholar 

  15. Rossel, M. & Capecchi, M. R. Mice mutant for both Hoxa1 and Hoxb1 show extensive remodeling of the hindbrain and defects in craniofacial development. Development 126, 5027–5040 (1999)

    CAS  PubMed  Google Scholar 

  16. Prasad, A. & Hollyday, M. Development and migration of avian sympathetic preganglionic neurons. J. Comp. Neurol. 307, 237–258 (1991)

    Article  CAS  PubMed  Google Scholar 

  17. Tsuchida, T. et al. Topographic organization of embryonic motor neurons defined by expression of LIM homeobox genes. Cell 79, 957–970 (1994)

    Article  CAS  PubMed  Google Scholar 

  18. William, C. M., Tanabe, Y. & Jessell, T. M. Regulation of motor neuron subtype identity by repressor activity of Mnx class homeodomain proteins. Development 130, 1523–1536 (2003)

    Article  CAS  PubMed  Google Scholar 

  19. Niederreither, K., McCaffery, P., Drager, U. C., Chambon, P. & Dolle, P. Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development. Mech. Dev. 62, 67–78 (1997)

    Article  CAS  PubMed  Google Scholar 

  20. Sockanathan, S. & Jessell, T. M. Motor neuron-derived retinoid signaling specifies the subtype identity of spinal motor neurons. Cell 94, 503–514 (1998)

    Article  CAS  PubMed  Google Scholar 

  21. Hart, K. C. et al. Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4. Oncogene 19, 3309–3320 (2000)

    Article  CAS  PubMed  Google Scholar 

  22. Gabay, L., Seger, R. & Shilo, B. Z. MAP kinase in situ activation atlas during Drosophila embryogenesis. Development 124, 3535–3541 (1997)

    CAS  PubMed  Google Scholar 

  23. Cai, J. et al. Evidence for the differential regulation of Nkx-6.1 expression in the ventral spinal cord and foregut by Shh-dependent and -independent mechanisms. Genesis 27, 6–11 (2000)

    Article  CAS  PubMed  Google Scholar 

  24. Arber, S. et al. Requirement for the homeobox gene Hb9 in the consolidation of motor neuron identity. Neuron 23, 659–674 (1999)

    Article  CAS  PubMed  Google Scholar 

  25. Jaynes, J. B. & O'Farrell, P. H. Active repression of transcription by the engrailed homeodomain protein. EMBO J. 10, 1427–1433 (1991)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sockanathan, S., Perlmann, T. & Jessell, T. M. Retinoid receptor signaling in postmitotic motor neurons regulates rostrocaudal positional identity and axonal projection pattern. Neuron 40, 97–111 (2003)

    Article  CAS  PubMed  Google Scholar 

  27. Kostic, D. & Capecchi, M. R. Targeted disruptions of the murine Hoxa-4 and Hoxa-6 genes result in homeotic transformations of components of the vertebral column. Mech. Dev. 46, 231–247 (1994)

    Article  CAS  PubMed  Google Scholar 

  28. Garcia-Gasca, A. & Spyropoulos, D. D. Differential mammary morphogenesis along the anteroposterior axis in Hoxc6 gene targeted mice. Dev. Dyn. 219, 261–276 (2000)

    Article  CAS  PubMed  Google Scholar 

  29. Chen, F. & Capecchi, M. R. Hoxa9, Hoxb9, and Hoxd9, function together to control development of the mammary gland in response to pregnancy. Proc. Natl Acad. Sci. USA 96, 541–546 (1999)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  30. Suemori, H. & Noguchi, S. Hox C cluster genes are dispensable for overall body plan of mouse embryonic development. Dev. Biol. 220, 333–342 (2000)

    Article  CAS  PubMed  Google Scholar 

  31. Lance-Jones, C., Omelchenko, N., Bailis, A., Lynch, S. & Sharma, K. Hoxd10 induction and regionalization in the developing lumbosacral spinal cord. Development 128, 2255–2268 (2001)

    CAS  PubMed  Google Scholar 

  32. Carpenter, E. M. Hox genes and spinal cord development. Dev. Neurosci. 24, 24–34 (2002)

    Article  CAS  PubMed  Google Scholar 

  33. Briscoe, J., Pierani, A., Jessell, T. M. & Ericson, J. A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube. Cell 101, 435–445 (2000)

    Article  CAS  PubMed  Google Scholar 

  34. Muhr, J., Andersson, E., Persson, M., Jessell, T. M. & Ericson, J. Groucho-mediated transcriptional repression establishes progenitor cell pattern and neuronal fate in the ventral neural tube. Cell 104, 861–873 (2001)

    Article  CAS  PubMed  Google Scholar 

  35. Goddard, J. M., Rossel, M., Manley, N. R. & Capecchi, M. R. Mice with targeted disruption of Hoxb-1 fail to form the motor nucleus of the VIIth nerve. Development 122, 3217–3228 (1996)

    CAS  PubMed  Google Scholar 

  36. Cooper, K. L., Leisenring, W. M. & Moens, C. B. Autonomous and nonautonomous functions for Hox/Pbx in branchiomotor neuron development. Dev. Biol. 253, 200–213 (2003)

    Article  CAS  PubMed  Google Scholar 

  37. Duboule, D. & Morata, G. Colinearity and functional hierarchy among genes of the homeotic complexes. Trends Genet. 10, 358–364 (1994)

    Article  CAS  PubMed  Google Scholar 

  38. Kmita, M. & Duboule, D. Organizing axes in time and space; 25 years of colinear tinkering. Science 301, 331–333 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  39. Jegalian, B. G. & De Robertis, E. M. Homeotic transformations in the mouse induced by overexpression of a human Hox3.3 transgene. Cell 71, 901–910 (1992)

    Article  CAS  PubMed  Google Scholar 

  40. Cohn, M. J., Izpisua-Belmonte, J. C., Abud, H., Heath, J. K. & Tickle, C. Fibroblast growth factors induce additional limb development from the flank of chick embryos. Cell 80, 739–746 (1995)

    Article  CAS  PubMed  Google Scholar 

  41. Cohn, M. J. et al. Hox9 genes and vertebrate limb specification. Nature 387, 97–101 (1997)

    Article  ADS  CAS  PubMed  Google Scholar 

  42. Kania, A. & Jessell, T. M. Topographic motor projections in the limb imposed by LIM homeodomain protein regulation of ephrin-A:EphA interactions. Neuron 38, 581–596 (2003)

    Article  CAS  PubMed  Google Scholar 

  43. Hollyday, M. & Jacobson, R. D. Location of motor pools innervating chick wing. J. Comp. Neurol. 302, 575–588 (1990)

    Article  CAS  PubMed  Google Scholar 

  44. Wahba, G. M., Hostikka, S. L. & Carpenter, E. M. The paralogous Hox genes Hoxa10 and Hoxd10 interact to pattern the mouse hindlimb peripheral nervous system and skeleton. Dev. Biol. 231, 87–102 (2001)

    Article  CAS  PubMed  Google Scholar 

  45. Tiret, L., Le Mouellic, H., Maury, M. & Brulet, P. Increased apoptosis of motoneurons and altered somatotopic maps in the brachial spinal cord of Hoxc-8-deficient mice. Development 125, 279–291 (1998)

    CAS  PubMed  Google Scholar 

  46. Mann, R. S. & Affolter, M. Hox proteins meet more partners. Curr. Opin. Genet. Dev. 8, 423–429 (1998)

    Article  CAS  PubMed  Google Scholar 

  47. Nelson, C. E. et al. Analysis of Hox gene expression in the chick limb bud. Development 122, 1449–1466 (1996)

    CAS  PubMed  Google Scholar 

  48. Brend, T., Gilthorpe, J., Summerbell, D. & Rigby, P. W. Multiple levels of transcriptional and post-transcriptional regulation are required to define the domain of Hoxb4 expression. Development 130, 2717–2728 (2003)

    Article  CAS  PubMed  Google Scholar 

  49. Li, X. & McGinnis, W. Activity regulation of Hox proteins, a mechanism for altering functional specificity in development and evolution. Proc. Natl Acad. Sci. USA 96, 6802–6807 (1999)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank F. Lo for technical assistance; C. Tabin for chick Hox in situ probes; and E. Laufer for advice and critical reagents. We thank R. Axel, J. DeNooij, J. Ericson, E. Laufer, R. Mann, B. Novitch and S. Wilson for comments, and K. MacArthur for help in preparing the manuscript. J.-P.L. is supported by a grant from NINDS and is a recipient of a Burroughs Wellcome Fund Career Award in Biomedical Sciences. J.D. is a research associate and T.M.J. an investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Jeremy S. Dasen or Thomas M. Jessell.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dasen, J., Liu, JP. & Jessell, T. Motor neuron columnar fate imposed by sequential phases of Hox-c activity. Nature 425, 926–933 (2003). https://doi.org/10.1038/nature02051

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature02051

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing