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Nr2f transcription factors promote the identity of the vertebrate upper jaw

ABSTRACT: The jaws are complementary in form and function but develop asymmetrically, as the lower but not upper jaw bone forms around a prominent cartilage template. How such differences in skeletal composition are patterned is unclear. Here, we identify four Nuclear receptor 2f genes, nr2f1a, nr2f1b, nr2f2, and nr2f5, as enriched in zebrafish upper jaw precursors. Whereas loss of Nr2f genes results in expansion of upper jaw cartilage to resemble that of the lower jaw, Nr2f5 misexpression inhibits lower jaw cartilage formation. Genome-wide analyses show that Nr2f genes prevent expansion of lower jaw-associated gene expression into the upper jaw territory. Further, restriction of Nr2f expression by Endothelin1 signaling is critical for lower jaw development, as reducing Nr2f dosage fully restores lower jaw development in edn1 mutants. We propose that Nr2f genes drive jaw asymmetry by limiting early cartilage differentiation in the upper jaw to preserve more precursors for later osteogenesis.

ORGANISM(S): Danio rerio

PROVIDER: GSE101719 | GEO | 2018/01/18

SECONDARY ACCESSION(S): PRJNA395253

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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Nr2f transcription factors promote the identity of the vertebrate upper jaw

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