Development, Vol 127, Issue 22 4855-4866, Copyright © 2000 by Company of Biologists

JOURNAL ARTICLES

Regulation of the neural patterning activity of sonic hedgehog by secreted BMP inhibitors expressed by notochord and somites

KF Liem, TM Jessell and J Briscoe
Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Center for Neurobiology and Behavior, Columbia University, New York, NY 10032, USA.

The secretion of Sonic hedgehog (Shh) from the notochord and floor plate appears to generate a ventral-to-dorsal gradient of Shh activity that directs progenitor cell identity and neuronal fate in the ventral neural tube. In principle, the establishment of this Shh activity gradient could be achieved through the graded distribution of the Shh protein itself, or could depend on additional cell surface or secreted proteins that modify the response of neural cells to Shh. Cells of the neural plate differentiate from a region of the ectoderm that has recently expressed high levels of BMPs, raising the possibility that prospective ventral neural cells are exposed to residual levels of BMP activity. We have examined whether modulation of the level of BMP signaling regulates neural cell responses to Shh, and thus might contribute to the patterning of cell types in the ventral neural tube. Using an in vitro assay of neural cell differentiation we show that BMP signaling markedly alters neural cell responses to Shh signals, eliciting a ventral-to-dorsal switch in progenitor cell identity and neuronal fate. BMP signaling is regulated by secreted inhibitory factors, including noggin and follistatin, both of which are expressed in or adjacent to the neural plate. Conversely, follistatin but not noggin produces a dorsal-to-ventral switch in progenitor cell identity and neuronal fate in response to Shh both in vitro and in vivo. These results suggest that the specification of ventral neural cell types depends on the integration of Shh and BMP signaling activities. The net level of BMP signaling within neural tissue may be regulated by follistatin and perhaps other BMP inhibitors secreted by mesodermal cell types that flank the ventral neural tube.

This article has been cited by other articles:

				K. Ohyama, R. Das, and M. Placzek Temporal progression of hypothalamic patterning by a dual action of BMP Development, October 15, 2008; 135(20): 3325 - 3331. [Abstract] [Full Text] [PDF]

				A. Bithell, S. E. Finch, M. F. Hornby, and B. P. Williams Fibroblast Growth Factor 2 Maintains the Neurogenic Capacity of Embryonic Neural Progenitor Cells In Vitro but Changes Their Neuronal Subtype Specification Stem Cells, June 1, 2008; 26(6): 1565 - 1574. [Abstract] [Full Text] [PDF]

				L. Garcia-Campmany and E. Marti The TGF{beta} intracellular effector Smad3 regulates neuronal differentiation and cell fate specification in the developing spinal cord Development, January 1, 2007; 134(1): 65 - 75. [Abstract] [Full Text] [PDF]

				P. Alexandre, I. Bachy, M. Marcou, and M. Wassef Positive and negative regulations by FGF8 contribute to midbrain roof plate developmental plasticity Development, August 1, 2006; 133(15): 2905 - 2913. [Abstract] [Full Text] [PDF]

				K. Fukuda and S. Yuasa Stem Cells as a Source of Regenerative Cardiomyocytes Circ. Res., April 28, 2006; 98(8): 1002 - 1013. [Abstract] [Full Text] [PDF]

				K. Ohyama, P. Ellis, S. Kimura, and M. Placzek Directed differentiation of neural cells to hypothalamic dopaminergic neurons Development, December 1, 2005; 132(23): 5185 - 5197. [Abstract] [Full Text] [PDF]

				L. M. Zeltser Shh-dependent formation of the ZLI is opposed by signals from the dorsal diencephalon Development, May 1, 2005; 132(9): 2023 - 2033. [Abstract] [Full Text] [PDF]

				R. Spoelgen, A. Hammes, U. Anzenberger, D. Zechner, O. M. Andersen, B. Jerchow, and T. E. Willnow LRP2/megalin is required for patterning of the ventral telencephalon Development, January 15, 2005; 132(2): 405 - 414. [Abstract] [Full Text] [PDF]

				J. Jeong and A. P. McMahon Growth and pattern of the mammalian neural tube are governed by partially overlapping feedback activities of the hedgehog antagonists patched 1 and Hhip1 Development, January 1, 2005; 132(1): 143 - 154. [Abstract] [Full Text] [PDF]

				J. Samanta and J. A. Kessler Interactions between ID and OLIG proteins mediate the inhibitory effects of BMP4 on oligodendroglial differentiation Development, September 1, 2004; 131(17): 4131 - 4142. [Abstract] [Full Text] [PDF]

				V. V. Chizhikov and K. J. Millen Control of Roof Plate Development and Signaling by Lmx1b in the Caudal Vertebrate CNS J. Neurosci., June 23, 2004; 24(25): 5694 - 5703. [Abstract] [Full Text] [PDF]

				O. V. Bulgakov, J. T. Eggenschwiler, D.-H. Hong, K. V. Anderson, and T. Li FKBP8 is a negative regulator of mouse sonic hedgehog signaling in neural tissues Development, May 1, 2004; 131(9): 2149 - 2159. [Abstract] [Full Text] [PDF]

				S. Chandran, H. Kato, D. Gerreli, A. Compston, C. N. Svendsen, and N. D. Allen FGF-dependent generation of oligodendrocytes by a hedgehog-independent pathway Development, December 29, 2003; 130(26): 6599 - 6609. [Abstract] [Full Text] [PDF]

				D.-W. Kim and A. B. Lassar Smad-Dependent Recruitment of a Histone Deacetylase/Sin3A Complex Modulates the Bone Morphogenetic Protein-Dependent Transcriptional Repressor Activity of Nkx3.2 Mol. Cell. Biol., December 1, 2003; 23(23): 8704 - 8717. [Abstract] [Full Text] [PDF]

				L. Ciani, A. Patel, N. D. Allen, and C. ffrench-Constant Mice Lacking the Giant Protocadherin mFAT1 Exhibit Renal Slit Junction Abnormalities and a Partially Penetrant Cyclopia and Anophthalmia Phenotype Mol. Cell. Biol., May 15, 2003; 23(10): 3575 - 3582. [Abstract] [Full Text] [PDF]

				S. Mekki-Dauriac, E. Agius, P. Kan, and P. Cochard Bone morphogenetic proteins negatively control oligodendrocyte precursor specification in the chick spinal cord Development, March 13, 2003; 129(22): 5117 - 5130. [Abstract] [Full Text] [PDF]

				J. R. Timmer, C. Wang, and L. Niswander BMP signaling patterns the dorsal and intermediate neural tube via regulation of homeobox and helix-loop-helix transcription factors Development, March 7, 2003; 129(10): 2459 - 2472. [Abstract] [Full Text] [PDF]

				M. Wijgerde, J. A. McMahon, M. Rule, and A. P. McMahon A direct requirement for Hedgehog signaling for normal specification of all ventral progenitor domains in the presumptive mammalian spinal cord Genes & Dev., November 15, 2002; 16(22): 2849 - 2864. [Abstract] [Full Text] [PDF]

				M. Persson, D. Stamataki, P. te Welscher, E. Andersson, J. Bose, U. Ruther, J. Ericson, and J. Briscoe Dorsal-ventral patterning of the spinal cord requires Gli3 transcriptional repressor activity Genes & Dev., November 15, 2002; 16(22): 2865 - 2878. [Abstract] [Full Text] [PDF]

				M. Rallu, R. Machold, N. Gaiano, J. G. Corbin, A. P. McMahon, and G. Fishell Dorsoventral patterning is established in the telencephalon of mutants lacking both Gli3 and Hedgehog signaling Development, January 11, 2002; 129(21): 4963 - 4974. [Abstract] [Full Text] [PDF]

				R. Adler and T. L. Belecky-Adams The role of bone morphogenetic proteins in the differentiation of the ventral optic cup Development, January 7, 2002; 129(13): 3161 - 3171. [Abstract] [Full Text] [PDF]

				J. B. Rubin, Y. Choi, and R. A. Segal Cerebellar proteoglycans regulate sonic hedgehog responses during development Development, January 5, 2002; 129(9): 2223 - 2232. [Abstract] [Full Text] [PDF]

				N. Gregori, C. Proschel, M. Noble, and M. Mayer-Proschel The Tripotential Glial-Restricted Precursor (GRP) Cell and Glial Development in the Spinal Cord: Generation of Bipotential Oligodendrocyte-Type-2 Astrocyte Progenitor Cells and Dorsal-Ventral Differences in GRP Cell Function J. Neurosci., January 1, 2002; 22(1): 248 - 256. [Abstract] [Full Text] [PDF]

				N. Sato, P. L. Leopold, and R. G. Crystal Effect of Adenovirus-Mediated Expression of Sonic Hedgehog Gene on Hair Regrowth in Mice With Chemotherapy-Induced Alopecia J Natl Cancer Inst, December 19, 2001; 93(24): 1858 - 1864. [Abstract] [Full Text] [PDF]