B1 SOX Coordinate Cell Specification with Patterning and Morphogenesis in the Early Zebrafish Embryo

Abstract

The B1 SOX transcription factors SOX1/2/3/19 have been implicated in various processes of early embryogenesis. However, their regulatory functions in stages from the blastula to early neurula remain largely unknown, primarily because loss-of-function studies have not been informative to date. In our present study, we systematically knocked down the B1 sox genes in zebrafish. Only the quadruple knockdown of the four B1 sox genes sox2/3/19a/19b resulted in very severe developmental abnormalities, confirming that the B1 sox genes are functionally redundant. We characterized the sox2/3/19a/19b quadruple knockdown embryos in detail by examining the changes in gene expression through in situ hybridization, RT–PCR, and microarray analyses. Importantly, these phenotypic analyses revealed that the B1 SOX proteins regulate the following distinct processes: (1) early dorsoventral patterning by controlling bmp2b/7; (2) gastrulation movements via the regulation of pcdh18a/18b and wnt11, a non-canonical Wnt ligand gene; (3) neural differentiation by regulating the Hes-class bHLH gene her3 and the proneural-class bHLH genes neurog1 (positively) and ascl1a (negatively), and regional transcription factor genes, e.g., hesx1, zic1, and rx3; and (4) neural patterning by regulating signaling pathway genes, cyp26a1 in RA signaling, oep in Nodal signaling, shh, and mdkb. Chromatin immunoprecipitation analysis of the her3, hesx1, neurog1, pcdh18a, and cyp26a1 genes further suggests a direct regulation of these genes by B1 SOX. We also found an interesting overlap between the early phenotypes of the B1 sox quadruple knockdown embryos and the maternal-zygotic spg embryos that are devoid of pou5f1 activity. These findings indicate that the B1 SOX proteins control a wide range of developmental regulators in the early embryo through partnering in part with Pou5f1 and possibly with other factors, and suggest that the B1 sox functions are central to coordinating cell fate specification with patterning and morphogenetic processes occurring in the early embryo.

C. elegansSoxB genes are dispensable for embryonic neurogenesis but required for terminal differentiation of specific neuron types

“…S3A). These findings are in striking contrast to the early neurogenic defects observed upon removal of Drosophila or vertebrate SoxB genes (Buescher et al, 2002;Bylund et al, 2003;Okuda et al, 2010;Overton et al, 2002;Pevny and Placzek, 2005). The apparent lack of requirement for C. elegans SoxB genes in overall neurogenesis is consistent with their limited and relatively late expression during embryonic nervous system development, as described above.…”

Wnt signaling andtbx16form a bistable switch to commit bipotential progenitors to mesoderm

“…2D-G), suggesting that Tbx16 actively inhibits progenitor cell gene expression. sox2 is also expressed in the neural tube, where it plays an important role in neural cell differentiation (Okuda et al, 2010). However, neural tube expression of sox2 was unaffected by ectopic tbx16, as was the notochord expression of ntl.…”

Molecular Mechanisms Regulating Impaired Neurogenesis of Fragile X Syndrome Human Embryonic Stem Cells

“…One of the molecular pathways activated by morphogens such as Shh and Noggin is the expression of the SOX superfamily of transcription factors, which in turn drive the progression of neural development [20,21,[41][42][43]. We have previously shown that FX-hESCs fail to upregulate SOX1 during IVND, concomitant with FMR1 downregulation [17].…”