Abstract
Cleft palate, a common global congenital malformation, occurs due to disturbances in palatal growth, elevation, contact, and fusion during palatogenesis. The Fibroblast growth factor 9 (FGF9) mutation has been discovered in humans with cleft lip and palate. Fgf9 is expressed in both the epithelium and mesenchyme, with temporospatial diversity during palatogenesis. However, the specific role of Fgf9 in palatogenesis has not been extensively discussed. Herein, we used Ddx4-Cre mice to generate an Fgf9–/– mouse model (with an Fgf9 exon 2 deletion) that exhibited a craniofacial syndrome involving a cleft palate and deficient mandibular size with 100% penetrance. A smaller palatal shelf size, delayed palatal elevation, and contact failure were investigated to be the intrinsic causes for cleft palate. Hyaluronic acid accumulation in the extracellular matrix (ECM) sharply decreased, while the cell density correspondingly increased in Fgf9–/– mice. Additionally, significant decreases in cell proliferation were discovered in not only the palatal epithelium and mesenchyme but also among cells in Meckel’s cartilage and around the mandibular bone in Fgf9–/– mice. Serial sections of embryonic heads dissected at embryonic day 14.5 (E14.5) were subjected to craniofacial morphometric measurement. This highlighted the reduced oral volume owing to abnormal tongue size and descent, and insufficient mandibular size, which disturbed palatal elevation in Fgf9–/– mice. These results indicate that Fgf9 facilitates palatal growth and timely elevation by regulating cell proliferation and hyaluronic acid accumulation. Moreover, Fgf9 ensures that the palatal elevation process has adequate space by influencing tongue descent, tongue morphology, and mandibular growth.
Highlights
Cleft lip and/or palate is a common congenital birth defect affecting approximately 1 in 700 newborns (Dixon et al, 2011)
By dissecting pregnant Fgf9+/− mice that had mated with male Fgf9+/− mice, we harvested Fgf9−/− embryos which died shortly after birth with a significant cleft secondary palate
These results revealed a successfully established Fgf9 knockout mouse model exhibiting cleft secondary palate, smaller mandible size, occipital deficiency, premature parietal ossification, and malformed premaxilla
Summary
Cleft lip and/or palate is a common congenital birth defect affecting approximately 1 in 700 newborns (Dixon et al, 2011). Effort has been made to explore the possible genetic factors responsible for cleft palate in mice, which represent the optimum model for identifying the underlying mechanism in humans (Juriloff and Harris, 2008; Burg et al, 2016; Li et al, 2019). The 22 members of the fibroblast growth factor (FGF) family participate in multiple aspects of palate development. Mutations in these factors are involved in 3–5% of cases of non-syndromic cleft lip and palate in humans (Riley et al, 2007; Wu et al, 2015; Jin et al, 2018; Weng et al, 2018). Cleft palate has been observed in Fgf9−/− mice with 40% penetrance, but the underlying mechanism has not been elaborated (Colvin et al, 2001)
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