Disc1 regulates foxd3 and sox10 expression, affecting neural crest migration and differentiation.
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.
Drerup
Catherine M
CM
Program in Human Molecular Genetics, Department of Pediatrics, Feinberg School of Medicine, Children's Memorial Research Center, Northwestern University, 2300 Children's Plaza, Chicago, IL 60614, USA.
Wiora
Heather M
HM
Topczewski
Jacek
J
Morris
Jill A
JA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D055785:Gene Knockdown Techniques; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009432:Neural Crest / Q000166:cytology* / Q000187:drug effects; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D022821:RNA Splice Sites; D055757:SOXE Transcription Factors / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012886:Skull / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism*
D015415:Biomarkers; C538728:DISC1 protein, zebrafish; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D022821:RNA Splice Sites; D055757:SOXE Transcription Factors; D029961:Zebrafish Proteins; C491002:foxd3 protein, zebrafish; C442229:sox10 protein, zebrafish