The transcription factor Sox10 is a key regulator of peripheral glial development.
Journal: 2001/February - Genes and Development
ISSN: 0890-9369
PUBMED: 11156606
Abstract:
The molecular mechanisms that determine glial cell fate in the vertebrate nervous system have not been elucidated. Peripheral glial cells differentiate from pluripotent neural crest cells. We show here that the transcription factor Sox10 is a key regulator in differentiation of peripheral glial cells. In mice that carry a spontaneous or a targeted mutation of Sox10, neuronal cells form in dorsal root ganglia, but Schwann cells or satellite cells are not generated. At later developmental stages, this lack of peripheral glial cells results in a severe degeneration of sensory and motor neurons. Moreover, we show that Sox10 controls expression of ErbB3 in neural crest cells. ErbB3 encodes a Neuregulin receptor, and down-regulation of ErbB3 accounts for many changes in development of neural crest cells observed in Sox10 mutant mice. Sox10 also has functions not mediated by ErbB3, for instance in the melanocyte lineage. Phenotypes observed in heterozygous mice that carry a targeted Sox10 null allele reproduce those observed in heterozygous Sox10(Dom) mice. Haploinsufficiency of Sox10 can thus cause pigmentation and megacolon defects, which are also observed in Sox10(Dom)/+ mice and in patients with Waardenburg-Hirschsprung disease caused by heterozygous SOX10 mutations.
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Genes Dev 15(1): 66-78

The transcription factor Sox10 is a key regulator of peripheral glial development

Max-Delbrück-Center for Molecular Medicine, D-13122 Berlin, Germany; Institut für Biochemie, Universität Erlangen-Nürnberg, D-91054 Erlangen Germany; Zentrum für Molekulare Neurobiologie, D-20246 Hamburg, Germany; Max-Planck-Institut für Experimentelle Medizin, D-37075 Göttingen, Germany
These authors contributed equally to this work.
Corresponding authors.
Received 2000 Jul 2; Accepted 2000 Nov 16.

Abstract

The molecular mechanisms that determine glial cell fate in the vertebrate nervous system have not been elucidated. Peripheral glial cells differentiate from pluripotent neural crest cells. We show here that the transcription factor Sox10 is a key regulator in differentiation of peripheral glial cells. In mice that carry a spontaneous or a targeted mutation of Sox10, neuronal cells form in dorsal root ganglia, but Schwann cells or satellite cells are not generated. At later developmental stages, this lack of peripheral glial cells results in a severe degeneration of sensory and motor neurons. Moreover, we show that Sox10 controls expression of ErbB3 in neural crest cells. ErbB3 encodes a Neuregulin receptor, and down-regulation of ErbB3 accounts for many changes in development of neural crest cells observed in Sox10 mutant mice. Sox10 also has functions not mediated by ErbB3, for instance in the melanocyte lineage. Phenotypes observed in heterozygous mice that carry a targeted Sox10 null allele reproduce those observed in heterozygous Sox10 mice. Haploinsufficiency of Sox10 can thus cause pigmentation and megacolon defects, which are also observed in Sox10/+ mice and in patients with Waardenburg-Hirschsprung disease caused by heterozygous SOX10 mutations.

Keywords: {Sox10, neuregulin, erbB3, neural crest, glial cells, melanocytes
Abstract

Neural crest cells detach from the dorsal neural tube and migrate over large distances in the embryo, using characteristic pathways. On arrival at their targets, they differentiate to form the majority of the peripheral nervous system, as well as other cell types and tissues including melanocytes (Le Douarin and Kalcheim 1999). Glial cells of the peripheral nervous system are generated by neural crest cells. These glia include satellite cells located in ganglia as well as Schwann cells, which ensheath peripheral axons. The differentiation of glial cells is thought to be regulated by the neurons they accompany. In vitro, transient activation of Notch signaling suffices to suppress the neurogenic differentiation of neural crest cells and accelerates glial differentiation (Morrison et al. 2000; Wakamatsu et al. 2000). Moreover, differentiation of neural crest cells into glia is promoted by Neuregulin-1, an EGF-like factor that activates ErbB receptors (Shah et al. 1994). Melanocytes represent another major derivative of the neural crest. They originate as nonpigmented precursors and migrate along characteristic dorso-lateral pathways to the epidermis. Development of the melanocyte lineage has been well studied genetically, as mutations in genes essential for their development cause pigmentation defects easily identifiable in mice and man (Goding 2000).

Sox10 was found because of its sequence homology to transcription factors of the SRY family, which contain a DNA-binding domain of the high mobility group (HMG) box family (Kuhlbrodt et al. 1998a; Wegner 1999). As yet, >20 members of the Sox gene family have been identified in mammals, which play important roles in diverse developmental processes such as sex determination, chondrogenic differentiation, or hematopoiesis (Wegner 1999). Sox10 expression is initiated in neural crest cells as they dissociate from the neural tube, and expression is maintained during neural crest cell migration. Expression continues in the glial and melanocyte lineages, but Sox10 is turned off in many other neural crest cell derivatives (Herbarth et al. 1998; Kuhlbrodt et al. 1998a; Pusch et al. 1998). In the heterozygous state, spontaneous mutations of Sox10 interfere with the development of melanocytes and of the enteric nervous system, causing pigmentation changes and megacolon. Such mutations have been identified in mice, the Dominant megacolon mutation (Sox10Dom), and in patients afflicted with Waardenburg syndrome type 4 (Herbarth et al. 1998; Kuhlbrodt et al. 1998b; Pingault et al. 1998; Southard-Smith et al. 1998, 1999). Moreover, myelination defects in the central and peripheral nervous systems were noted in certain patients with heterozygous Sox10 mutations (Inoue et al. 1999; Pingault et al. 2000; Touraine et al. 2000). In accordance, Sox10 controls expression of myelin protein genes like P0 and binds to the P0 promoter (Peirano et al. 2000). Homozygous Sox10Dom mutant mice display severe deficits in the peripheral nervous system, which include a lack of enteric ganglia and a severe hypoplasia of the sympathetic ganglion chain (Herbarth et al. 1998; Southard-Smith et al. 1998; Kapur 1999).

The spontaneous Sox10 mutations characterized are nonsense or frameshift mutations. For instance, a frameshift mutation generated the murine Sox10Dom allele, which encodes a protein in which the N-terminal 193 amino acids of Sox10, including the HMG box, are preserved and fused to 99 amino acids encoded by a different reading frame (Herbarth et al. 1998; Southard-Smith et al. 1998). Similarly, known human Sox10 mutations are predicted to generate truncated proteins that retain functional sequences, such as a homodimerization domain, a synergy region, or the DNA-binding domain (Kuhlbrodt et al. 1998b; Pingault et al. 1998; Bondurand et al. 1999; Inoue et al. 1999; Southard-Smith et al. 1999; Peirano and Wegner 2000; Pingault et al. 2000; Touraine et al. 2000). Indeed, the proteins encoded by many of the spontaneously mutated Sox10 alleles have unaltered DNA-binding properties. It was therefore suggested that the developmental defects observed in Waardenburg-Hirschsprung disease are caused by a dominant-negative action of the mutant Sox10 protein (Kuhlbrodt et al. 1998b; Pingault et al. 1998; Southard-Smith et al. 1999).

ErbB3 encodes a member of the family of EGF receptor tyrosine kinases, binds Neuregulins with high affinity, and requires ErbB2 as a coreceptor for signaling in vivo (Adlkofer and Lai 2000; Garratt et al. 2000). The expression of ErbB3, like that of Sox10, is initiated in neural crest cells as they dissociate from the neural tube and is maintained in glia but downregulated in other derivatives of neural crest cells (Meyer and Birchmeier 1995; Meyer et al. 1997). Additional, nonoverlapping expression domains of Sox10 and ErbB3 in other tissues exist. ErbB3 mice and other mutants of the Neuregulin signaling system display defects in development of neural crest cells and their derivatives, which include a lack of Schwann cells (Erickson et al. 1997; Riethmacher et al. 1997; Britsch et al. 1998; Morris et al. 1999; Woldeyesus et al. 1999; Garratt et al. 2000; Wolpowitz et al. 2000). An additional, conspicuous phenotype in such mice is the degeneration of sensory and motor neurons. ErbB3 is required cell autonomously for the development of Schwann cells, but not for survival of sensory and motor neurons (Riethmacher et al. 1997). The neurodegeneration observed in such mutant mice is thus caused by indirect mechanisms.

We report here the generation of a targeted Sox10 mutation in mice, in which the complete open reading frame of Sox10 is replaced by lacZ sequences (Sox10lacZ). In a heterozygous state, the Sox10lacZ mutation causes phenotypes that reproduce those of the spontaneous Sox10Dom allele. Thus, haploinsufficiency can account for megacolon and pigmentation defects. In homozygous Sox10 mutant mice, sensory neurons form in dorsal root ganglia, but satellite cells or Schwann cells do not develop, demonstrating a key role of this transcription factor in the development of peripheral glial cells. The similarities in expression patterns of Sox10 and ErbB3 prompted us to investigate a genetic interaction between the two genes. We demonstrate here that appropriate ErbB3 expression in neural crest cells, but not in other tissues like muscle or skin, requires Sox10. In accordance, Sox10 and ErbB3 mutant mice share phenotypes. These include a conspicuous degeneration of sensory and motor neurons. This finding allows us to assign, unequivocally, a trophic function to glial cells in the maintenance of neurons.

Acknowledgments

We thank Cathrin Rudolph, Karin Gottschling, and Sven Buchert for expert technical assistance; Claus Stolt and Thomas Franz for experimental support; and A. Garratt for help with the writing of the manuscript. Special thanks go to Henning Brohmann and Li Li for supporting the project, to Martin Sieber for the statistical analysis, and Thomas Müller for the anti-B-FABP antibody. We obtained plasmids from the following scientists: p75 (L. Tessarollo and L. Reichardt), Notch-1 and Hes-5 (M. Hrabe de Angelis), Cadherin-6 (M. Takeichi), VAChT (D. Wolpowitz and J. Dedman), c-kit (M. Goossens), trp-2 and trp-2 promoter (I. Jackson). This work was supported by grants of the BMBF and DFG to C.B., M.W., and D.R.

The publication costs of this article were defrayed in part by payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 USC section 1734 solely to indicate this fact.

Acknowledgments

Footnotes

E-MAIL ed.nilreb-cdm@hcribc; FAX 49-30-9406-3765.

E-MAIL ed.negnalre-inu.mehcoib@rengew.m; FAX 49-9131-85-22484.

Article and publication are at www.genesdev.org/cgi/doi/10.1101/gad.186601.

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