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The Gq/11 family of G alpha subunits is necessary and sufficient for lower jaw development

ABSTRACT: Development of the vertebrate jaw apparatus depends on highly conserved signaling pathways. Patterning of the lower jaw is driven by Endothelin receptor type A (Ednra) and secreted ligand Endothelin 1 (Edn1). The Ednra signaling pathway establishes the identity of lower jaw progenitors by regulating expression of numerous patterning genes, but the intracellular signaling mechanisms linking receptor activation to gene regulation remains poorly understood. As a first step towards addressing this question, we examined the function of the Gq/11 family of Gα subunits in zebrafish using pharmacological and genetic ablation of Gq/11 activity and transgenic induction of a constitutively active Gq protein in edn1-/- embryos. Loss of Gq/11 activity fully recapitulated the edn1-/- phenotype, with genes encoding for G11 being most essential. Furthermore, inducing Gq activity in edn1-/- embryos not only restored Ednra-dependent jaw structures and gene expression signatures but also caused homeosis of the upper jaw structures into a lower jaw-like structure. These results indicate that Gq/11 is necessary and sufficient to mediate the lower jaw patterning mechanism for Ednra.

ORGANISM(S): Danio rerio

PROVIDER: GSE275013 | GEO | 2024/09/19

REPOSITORIES: GEO

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Project description:Distinct shaping of the upper versus lower facial skeleton is essential for function of the vertebrate jaw and middle ear, yet the cellular mechanisms by which this occurs have remained unclear. Here, we show that Endothelin1 (Edn1) signaling accelerates mesenchymal condensation and subsequent cartilage formation in the lower face through antagonism of Jagged-Notch signaling and Prrx1 transcription factors. A genomic analysis of facial skeletal precursors in mutants and overexpression embryos reveals that Jagged-Notch signaling represses genes that are strongly induced as pharyngeal arch neural crest-derived cells begin skeletal differentiation. In wild types, initial Jagged-Notch repression dorsally ensures that barx1+ condensations and cartilage differentiation occur first in ventral-intermediate zones of the pharyngeal arches. Reduced Jagged-Notch signaling results in an expansion of pre-cartilage condensations in the upper face, with loss of barx1 partially restoring dorsal cartilage shapes in jag1b mutants. Further, by studying new mutants for zebrafish prrx1a and prrx1b, we find that Prrx1 genes function in parallel to Jagged-Notch signaling to restrict the formation of dorsal barx1+ pre-cartilage condensations. Consistently, combined losses of jag1b and prrx1a/b robustly rescue ventral barx1+ condensations and lower facial cartilage development in edn1 mutants. Together, our work suggests that Edn1 works through parallel inhibition of Jagged-Notch and Prrx1 pathways to promote an earlier and more extensive establishment of cartilage condensations in the lower face. We performed RNAseq on FACS-sorted neural crest-derived pharyngeal arch cells (fli1a:GFP; sox10:DsRed double positive) from wild-type embryos at 3 different stages (20, 28, and 36 hours post fertilization) and embryos with altered levels of Edn1 and Notch signaling (edn1 mutants and hsp70I:Gal4; UAS:Edn1 transgenics; jag1b mutants, dibenzazepine-treated embryos, and hsp70I:Gal4; UAS:NICD transgenics. We also sequenced RNA from heat-shocked UAS:Edn1+ and hsp70I:Gal4+ transgenics and jag1b+/+ controls.

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The Gq/11 family of G alpha subunits is necessary and sufficient for lower jaw development

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