Disc1 regulatesfoxd3andsox10expression, affecting neural crest migration and differentiation

Abstract

This work reports the characterization and functional analysis of disrupted in schizophrenia 1 (disc1), a well-documented schizophrenia-susceptibility gene, in zebrafish cranial neural crest (CNC). Our data demonstrated that disc1 was expressed in zebrafish CNC cells. Loss of Disc1 resulted in persistent CNC cell medial migration, dorsal to the developing neural epithelium, and hindered migration away from the region dorsal to the neural rod. General CNC cell motility was not affected by Disc1 knockdown, however, as the speed of CNC cells was indistinguishable from that of wild-type counterparts. We determined that the failure of CNC cells to migrate away from the neural rod correlated with the enhanced expression of two transcription factors, foxd3 and sox10. These transcription factors have many functions in CNC cells, including the maintenance of precursor pools, timing of migration onset, and the induction of cell differentiation. Our work, in conjunction with previous studies, suggests that the perpetuation of expression of these factors affects several aspects of CNC cell development, leading to a loss of craniofacial cartilage and an expansion of peripheral cranial glia. Based on our data, we propose a model in which Disc1 functions in the transcriptional repression of foxd3 and sox10, thus mediating CNC cell migration and differentiation.

Schizophrenia and Human Self-Domestication: An Evolutionary Linguistics Approach

“…SOX9 acts specifically in craniofacial development, downstream of the WNT and bone morphogenic protein (BMP) pathways , and it has been found [Shao and Vawter, 2008;Chen et al, 2013;Lanz et al, 2013]. SOX10 regulates the NC stem cell balance during development; it is functionally related to the SZ susceptibility gene DISC1 during early NC cell migration [Drerup et al, 2009] and oligodendrocyte differentiation [Hattori et al, 2014]. SOX10 is found to be hypermethylated in the brain of SZ patients [Iwamoto et al, 2005] and carries singlenucleotide polymorphisms that have been related to the age of onset of clinical manifestations [Yuan et al, 2013].…”

“…functional status may have occurred during recent human evolution. FOXD3 is also a transcriptional target of the SZ candidate DISC1 , and it is involved in cranial NC migration and differentiation [Drerup et al, 2009]. SOX9 and SOX10 indirectly interact through FOXD3 , as shown in Figure 3 , being coexpressed at different stages of NC development.…”

Neural crest stem cell multipotency requires Foxd3 to maintain neural potential and repress mesenchymal fates

“…Sox10 expression is markedly reduced in both Foxd3 mutant embryos (Teng et al, 2008) and NC cultures. Although it is possible that Foxd3 may regulate Sox10 expression and vice versa, it is also likely that they are coordinately regulated (Drerup et al, 2009). Sox10 preservation of glial fates may act in synchrony with Foxd3-mediated maintenance of neural competency within NCSCs to ensure multipotency.…”

Understanding the Role of DISC1 in Psychiatric Disease and during Normal Development

“…Subsequent genetic studies have confirmed that the DISC locus is involved in multiple psychiatric disorders and cognitive function, in several populations worldwide (Chubb et al, 2008;Jaaro-Peled, 2009). Efforts to model DISC1 disease biology in transgenic mice, and more recently in Drosophila and zebrafish, have been quite successful (Sawamura et al, 2008;Wang et al, 2008;Drerup et al, 2009;Kellendonk et al, 2009). In general DISC1 mutant mice, from a range of approaches, show behavioral and anatomical deficits that can be linked to psychiatric disease.…”