Gremlin 2 regulates distinct roles of BMP and Endothelin 1 signaling in dorsoventral patterning of the facial skeleton.
Patterning of the upper versus lower face involves generating distinct pre-skeletal identities along the dorsoventral (DV) axes of the pharyngeal arches. Whereas previous studies have shown roles for BMPs, Endothelin 1 (Edn1) and Jagged1b-Notch2 in DV patterning of the facial skeleton, how these pathways are integrated to generate different skeletal fates has remained unclear. Here, we show that BMP and Edn1 signaling have distinct roles in development of the ventral and intermediate skeletons, respectively, of the zebrafish face. Using transgenic gain-of-function approaches and cell-autonomy experiments, we find that BMPs strongly promote hand2 and msxe expression in ventral skeletal precursors, while Edn1 promotes the expression of nkx3.2 and three Dlx genes (dlx3b, dlx5a and dlx6a) in intermediate precursors. Furthermore, Edn1 and Jagged1b pattern the intermediate and dorsal facial skeletons in part by inducing the BMP antagonist Gremlin 2 (Grem2), which restricts BMP activity to the ventral-most face. We therefore propose a model in which later cross-inhibitory interactions between BMP and Edn1 signaling, in part mediated by Grem2, separate an initially homogenous ventral region into distinct ventral and intermediate skeletal precursor domains.
Broad CIRM Center, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.
Elizabeth
E
Zuniga
Marie
M
Rippen
Courtney
C
Alexander
Thomas F
TF
Schilling
J Gage
JG
Crump
D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D019332:Endothelin-1 / Q000378:metabolism*; D005147:Facial Bones / Q000196:embryology*; D005786:Gene Expression Regulation / Q000502:physiology; D018398:Homeodomain Proteins / Q000378:metabolism; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D017931:DNA Primers; C088334:Distal-less homeobox proteins; D019332:Endothelin-1; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; C495207:Jag3 protein, zebrafish; D014157:Transcription Factors; D029961:Zebrafish Proteins; C414282:edn1 protein, zebrafish; C516331:grem2b protein, zebrafish