Distinct functions for Bmp signaling in lip and palate fusion in mice

TLDR

Cleft lip with or without cleft palate is genetically distinct from isolated cleft secondary palate, and mutations in the Bmp target gene Msx1 implicate Bmp signaling in both conditions. The study aimed to dissect Bmp signaling function in orofacial clefting by conditionally inactivating the type 1 Bmp receptor Bmpr1a in facial primordia using a Nestin Cre transgenic line. Conditional inactivation of Bmpr1a in facial primordia was achieved via Nestin Cre, creating a mouse model to probe Bmp pathway roles. Nestin Cre; Bmpr1a mutants exhibited fully penetrant bilateral CL/P with arrested tooth formation; cleft secondary palate showed reduced proliferation and defective patterning, while increased apoptosis occurred in the fusing medial nasal process; conditional Bmp4 inactivation caused isolated cleft lip, revealing a Bmp4‑Bmpr1a pathway essential for lip fusion and distinct Bmp roles in lip versus palate fusion.

Abstract

Previous work suggested that cleft lip with or without cleft palate (CL/P)is genetically distinct from isolated cleft secondary palate (CP). Mutations in the Bmp target gene Msx1 in families with both forms of orofacial clefting has implicated Bmp signaling in both pathways. To dissect the function of Bmp signaling in orofacial clefting, we conditionally inactivated the type 1 Bmp receptor Bmpr1a in the facial primordia, using the Nestin cre transgenic line. Nestin cre; Bmpr1amutants had completely penetrant, bilateral CL/P with arrested tooth formation. The cleft secondary palate of Nestin cre; Bmpr1amutant embryos was associated with diminished cell proliferation in maxillary process mesenchyme and defective anterior posterior patterning. By contrast,we observed elevated apoptosis in the fusing region of the Nestin cre; Bmpr1a mutant medial nasal process. Moreover, conditional inactivation of the Bmp4 gene using the Nestin cretransgenic line resulted in isolated cleft lip. Our data uncover a Bmp4-Bmpr1a genetic pathway that functions in lip fusion, and reveal that Bmp signaling has distinct roles in lip and palate fusion.