Expression of the< i> SOX10</i> gene during human development

FEBS Letters, 1998

SOX10, a new member of the SOX gene family, is a transcription factor defective in the Dom (Dominant megacolon) mouse and in the human Shah-Waardenburg syndrome. To help unravel its physiological role during human development, we studied SOX10 gene expression in embryonic, fetal, and adult human tissues by Northern blot and in situ hybridization. As in mice, the human SOX10 gene was essentially expressed in the neural crest derivatives that contribute to the formation of the peripheral nervous system, and in the adult central nervous system. Nevertheless, it was more widely expressed in humans than in rodents. The spatial and temporal pattern of SOX10 expression supports an important function in neural crest development.

Developmental Brain Research, 2000

Human SOX10 and mouse Sox10 have been cloned and shown to be expressed in the neural crest derivatives that contribute to formation of the peripheral nervous system during embryogenesis. Mutations in Sox10 have been identified as a cause of the Dominant megacolon mouse and Waardenburg-Shah syndrome in human, both of which include defects in the enteric nervous system and pigmentation (and in the latter, sometimes hearing). We have cloned a chick Sox10 ortholog (cSox10 ) in order to study its role in neural crest cell development. This cDNA reveals a 1383 bp open reading frame encoding 461 amino acids which is highly conserved with human SOX10 and mouse Sox10. In situ hybridization showed cSox10 is expressed in migrating neural crest cells just after the zinc finger transcription factor Slug, but is lost as cells undergo neuronal differentiation in ganglia of the peripheral nervous system. In addition, cSox10 is expressed in the developing otic vesicle, the developing central nervous system and pineal gland.

Developmental Biology, 2003

The Sox family of transcription factors has been implicated in the development of different tissues during embryogenesis. Several mutations in humans, mice, and zebrafish have shown that depletion of Sox10 activity produces defects in the development of neural crest derivatives, such as melanocytes, ganglia of the peripheral nervous system, and some specific cell types as glia. We have isolated the Xenopus homologue of the Sox10 gene. It is expressed in prospective neural crest and otic placode regions from the earliest stages of neural crest specification and in migrating cranial and trunk neural crest cells. Loss-of-function experiments using morpholino antisense oligos against Sox10 produce a loss of neural crest precursors and an enlargement of the surrounding neural plate and epidermis. This effect of Sox10 depletion is produced during some of the earliest steps of neural crest specification, as is shown by the inhibition in the expression of Slug and FoxD3, which are early markers of neural crest specification. In addition, we show that Sox10 depletion leads to an increase in apoptosis and a decrease in cell proliferation in the neural folds, suggesting that Sox10 could work as a survival as well as a specification factor in neural crest precursors during premigratory stages. Although some of the deficiencies found in the Waardenburg syndrome and in the Hirschprung disease could be associated with a failure of the development of crest derivatives during the late phase of its development, or even during adulthood, our results suggest that inhibition of Sox10 activity produces an earlier failure of neural crest precursors. In experiments where melanocytes and ganglia were induced in vivo and in vitro, we were able to block their development by inhibiting Sox10 activity. These results are compatible with an additional late role of Sox10 on development of neural crest derivatives, as it has been previously proposed. We show that Sox10 expression is dependent on FGF and Wnt activity, both in the neural crest and in the otic placode territories. Finally, in order to establish the position of Sox10 in the hierarchical cascade of gene activation required for neural crest specification, we used inducible forms of the wild type and dominant negatives for the Snail and Slug genes. Our results show that Snail is able to control Sox10 expression. However, the overexpression of Slug was not able to upregulate Sox10 expression. Taken together, these results indicate that Sox10 may lie between Snail and Slug in the genetic cascade that controls neural crest development.

Human molecular genetics, 2006

Developmental Dynamics, 2005

SoxE genes (Sox8, Sox9, and Sox10) are early response genes to neural crest induction. Although the early role of Sox9 has been examined in chick and frog, later roles in neural crest migration and differentiation remain largely unexplored. We first examined which SoxE genes were expressed in trunk neural crest cells and then investigated their function using in ovo electroporation. The results of this analysis reveal that Sox10 is present in migrating neural crest cells, whereas other SoxE genes are only expressed transiently after induction. Ectopic expression of Sox10 in the neural tube at trunk level induced expression of HNK-1 in neuroepithelial cells followed by extensive emigration from all levels of the dorsoventral neuraxis, including the floor plate. Sox10-expressing cells failed to express neuronal, Schwann, or melanocyte markers up to 6 days posttransfection (E8), suggesting these cells were maintained in an undifferentiated state. Overexpression of Sox8 or Sox9 had similar but not identical effects on neuroepithelial cells. These results show that high levels of Sox10, Sox9, or Sox8 expression in the neural tube are capable of inducing a migratory neural crest-like phenotype even in the absence of dorsal signals and can maintain these cells in an undifferentiated state. Developmental Dynamics 233: 430 -444, 2005.

Genes & Development, 2001

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.

Development, 2007

The transcription factor Sox10 regulates early neural crest development,specification of neural crest-derived lineages and terminal differentiation of oligodendrocytes in the central nervous system. Here, we generated two novel hypomorphic Sox10 alleles in the mouse. Mutant mice either expressed a Sox10 protein with a triple alanine substitution in the dimerization domain,or a Sox10 protein with a deletion in the central portion that we define as a cell-specific transactivation domain. Phenotypic analysis revealed important roles for a functional dimerization domain and the newly defined novel transactivation domain in melanocyte and enteric nervous system development,whereas early neural crest development and oligodendrocyte differentiation were surprisingly little disturbed in both mutants. Unique requirements were additionally detected for the novel transactivation domain in satellite glia differentiation and during Schwann cell myelination, whereas DNA-dependent dimerization was...

Human Molecular Genetics, 1997

SOX (SRY box-containing) genes share a particular DNA-binding domain, called HMG, with the mammalian testis-determining gene SRY. Several SOX genes have already been shown to be transcription factors involved in the decision of important cell fates during development. Here we report the cloning of a new human member of the SOX gene family, SOX22. The corresponding protein contains several domains that are also present in other paralogous SOX proteins. The SOX22 gene maps to chromosome 20 on band p13 and does not appear to be clustered with any other SOX gene mapped to date. SOX22 mRNA is expressed in various fetal and adult organs and tissues, suggesting that this gene plays roles in both differentiation and maintenance of several cell types.

Journal of Biological Chemistry, 1998

The Sry-related protein Sox10 is selectively expressed in neural crest cells during early stages of development and in glial cells of the peripheral and central nervous systems during late development and in the adult. Mutation of the Sox10 gene leads to neural crest defects in the Dominant megacolon mouse mutant and to combined Waardenburg-Hirschsprung syndrome in humans. Here, we have studied the four Sox10 mutations found to date in Waardenburg-Hirschsprung patients both in the context of the rat and the human cDNA. Unlike the rat Sox10 protein, which failed to show transcriptional activity on its own, human Sox10 displayed a weak, but reproducible, activity as a transcriptional activator. All mutant Sox10 proteins, including the one that only lacked the 106 last amino acids were deficient in this capacity, indicating that the carboxyl terminus of human Sox10 carries a transactivation domain. Whereas all four mutants failed to transactivate, only two failed to synergistically enhance the activity of other transcription factors. Synergy required both the ability to bind to DNA and a region in the amino-terminal part of Sox10. Those mutants that failed to synergize were unable to bind to DNA. Analysis of the naturally occurring Sox10 mutations not only helps to dissect Sox10 structure, but also allows limited predictions on the severity of the disease.

Molecular Brain Research, 2000

The transcription factor-encoding gene, Sox4, is expressed in a wide range of tissues and has been shown to be functionally involved in heart, B-cell and reproductive system development. Sox4 shows a high degree of sequence homology with another group C Sox gene, Sox11, which is predominantly expressed in the CNS. Since the expression of Sox4 in the CNS has not been described we have carried out such a study. Sox4 and Sox11 expression increased simultaneously in the same early differentiating cells of the developing CNS except in the external granule layer of the cerebellum where Sox11 expression preceded that of Sox4. As development proceeded, their expression always appeared to relate to the maturational stage of the cell population, with Sox11 expression more transient than Sox4, except in the spinal cord where the reverse was true. Sox4 knock-out mice have been shown to die of a heart defect half way through gestation with no observable CNS phenotype. Our more detailed analysis showed no abnormality in the spatial restriction of expression of Sox2, Sox11, Mash1, neurogenin1 or neurogenin2, although the level of expression of Sox11 and Mash1 appeared a little different from the wild-type, implying that Sox4 might indeed have a functional role in CNS development. However, since Sox4 and Sox11 expression is so similar, we propose that Sox11 might compensate for the loss of Sox4 function in the CNS such that the phenotype is extremely mild in the Sox4 null mutant.