The Fibroblast Growth Factor 9 (Fgf9) Participates in Palatogenesis by Promoting Palatal Growth and Elevation

Abstract

Cleft palate, a common global congenital malformation, occurs due to disturbances in palatal growth, elevation, contact, and fusion during palatogenesis. The <i>Fibroblast growth factor 9</i> (<i>FGF9</i>) mutation has been discovered in humans with cleft lip and palate. <i>Fgf9</i> is expressed in both the epithelium and mesenchyme, with temporospatial diversity during palatogenesis. However, the specific role of <i>Fgf9</i> in palatogenesis has not been extensively discussed. Herein, we used <i>Ddx4-Cre</i> mice to generate an <i>Fgf9^-/-</i> mouse model (with an <i>Fgf9</i> 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 <i>Fgf9^-/-</i> 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 <i>Fgf9^-/-</i> 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 <i>Fgf9^-/-</i> mice. These results indicate that <i>Fgf9</i> facilitates palatal growth and timely elevation by regulating cell proliferation and hyaluronic acid accumulation. Moreover, <i>Fgf9</i> ensures that the palatal elevation process has adequate space by influencing tongue descent, tongue morphology, and mandibular growth.