The Function and Regulatory Network ofPax9Gene in Palate Development

Abstract

Cleft palate, a common congenital deformity, can arise from disruptions in any stage of palatogenesis, including palatal shelf growth, elevation, adhesion, and fusion. Paired box gene 9 (Pax9) is recognized as a vital regulator of palatogenesis with great relevance to cleft palate in humans and mice. Pax9-deficient murine palatal shelves displayed deficient elongation, postponed elevation, failed contact, and fusion. Pax9 is expressed in epithelium and mesenchyme, exhibiting a dynamic expression pattern that changes according to the proceeding of palatogenesis. Recent studies highlighted the Pax9-related genetic interactions and their critical roles during palatogenesis. During palate growth, PAX9 interacts with numerous molecules and members of pathways (e.g., OSR2, FGF10, SHOS2, MSX1, BARX1, TGFβ3, LDB1, BMP, WNT β-catenin dependent, and EDA) in the mesenchyme and functions as a key mediator in epithelial-mesenchymal communications with FGF8, TBX1, and the SHH pathway. During palate elevation, PAX9 is hypothesized to mediate the time point of the elevation event in the anterior and posterior parts of the palatal shelves. The delayed elevation of Pax9 mutant palatal shelves probably results from abnormal expressions of a series of genes ( Osr2 and Bmpr1a) leading to deficient palate growth, abnormal tongue morphology, and altered hyaluronic acid distribution. The interactions between PAX9 and genes encoding the OSR2, TGFβ3, and WNT β-catenin-dependent pathways provide evidence that PAX9 might participate in the regulation of palate fusion. This review summarizes the current understanding of PAX9’s functions and emphasizes the interactions between PAX9 and vital genes during palatogenesis. We hope to provide some clues for further exploration of the function and mechanism of PAX9, especially during palate elevation and fusion events.

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

“…This communication is based on the overlaying of the Fgf9 and Fgfr2 expression patterns in the epithelium of the developing palate and the resultant in modulation of palatal cell proliferation by Fgf9-Fgfr2 (Huang et al, 2016;Weng et al, 2018). Additionally, Fgfr2 combined with Fgf10, which is expressed in the palatal mesenchyme, along with Shh, plays an essential role in EMC (Colvin et al, 2001;Li et al, 2019). Studies have shown that Fgf9 participates in the Shh-Fgfr2-Fgf10 pathway during lung, cecal, and inner ear development (Colvin et al, 2001;Pirvola et al, 2004;Al Alam et al, 2012).…”

“…For decades, there was a consensus that cell proliferation is the critical factor that induces palatal growth and that it is a requisite for palatal elevation (Li et al, 2019). However, in recent years continuous research has indicated the possible role of HA accumulation in ECM expansion; HA accumulation is no longer merely an internal force for palatal elevation but has emerged as a potential promoter of tissue expansion during palatal growth (Chiquet et al, 2016;Li et al, 2017;Lan et al, 2019;Yonemitsu et al, 2020).…”

“…Mice with cleft palate share similar developmental and genetic features with humans with cleft palate (Mittwoch, 2008). Secondary palate formation in both species is generally divided into three periods, comprising palatal growth and enlargement before embryonic day 13.5 (E13.5), elevation and contact before E14.5, and fusion before E15.5 (Li et al, 2019). Thus, 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).…”

Genetic Factors in Nonsyndromic Orofacial Clefts

“…PAX9 is located on chromosome 14q13.3, consists of five exons, and associated with the formation of the teeth and palate. 57,58 Tooth agenesis and the formation of a cleft palate in PAX9-deficient mice have been reported. 59 Schuffenhauer et al, first reported the role of PAX9 in a patient presented with bilateral CLP.…”

Three-dimensional reconstruction of systematic histological sections: application to observations on palatal shelf elevation

“…Because of the rapid process, the exact molecular mechanism still remains elusive. 1 – 5 Several hypotheses about the morphological changes have been considered for decades. Walker and Fraser proposed that the PS rapidly remodeled itself by bulging a new protrusion on the lingual wall and regression at the original tip, and described that the PS reorientation proceeded in a wave-liking manner from posterior to anterior.…”