Molecular signaling along the anterior-posterior axis of early palate development

Abstract

Cleft palate is a common congenital birth defect in humans. In mammals, the palatal tissue can be distinguished into anterior bony hard palate and posterior muscular soft palate that have specialized functions in occlusion, speech or swallowing. Regulation of palate development appears to be the result of distinct signaling and genetic networks in the anterior and posterior regions of the palate. Development and maintenance of expression of these region-specific genes is crucial for normal palate development. Numerous transcription factors and signaling pathways are now recognized as either anterior- (e.g., Msx1, Bmp4, Bmp2, Shh, Spry2, Fgf10, Fgf7, and Shox2) or posterior-specific (e.g., Meox2, Tbx22, and Barx1). Localized expression and function clearly highlight the importance of regional patterning and differentiation within the palate at the molecular level. Here, we review how these molecular pathways and networks regulate the anterior-posterior patterning and development of secondary palate. We hypothesize that the anterior palate acts as a signaling center in setting up development of the secondary palate.

Keywords: anterior–posterior axis; development; growth factors; migration; secondary palate; signaling.

Figure 1

Schematic representation for defining anterior, medial, and posterior regions of palatal shelves. Tissue anterior or posterior to first molar tooth is considered anterior or posterior palate, respectively. The palatal tissue in the region of first molar tooth bud is considered medial. Abbreviations: PP, primary palate; PS, palatal shelves; M1, first molar tooth bud.

Figure 2

Schematic representation of the key regulators in the anterior palate. Msx1 and Bmp4 function in an autoregulatory loop mechanism in the mesenchyme. Bmp4 induces Shh expression in the epithelium which signals backs to the mesenchyme to positively regulate Bmp2 to enhance cell proliferation in the mesenchyme. Msx1 expression is controlled by Hoxa2 in early palatal development. Fgfs and their receptors are regulated by Spry2 for proper balance of proliferation and prevention of premature apoptosis in the epithelium. Fgf10 induces Shh whereas Fgf7 acts as an antagonist. Msx1 also maintains proliferation by inducing Bmp7 in the mesenchyme along the nasal epithelium. Genes represented in red are restricted to either oral or nasal side of the palate, whereas those represented in blue are present across the shelf.

Figure 3

Schematic representation of the key regulators in the posterior palate. Barx1 and Tbx22 induce cell proliferation in the posterior palate. Hoxa2 also controls the expression of Barx1 in the early stage of palatogenesis. Mn1 positively regulates Tbx22 and represents the first network determined to specifically regulate the level of proliferation in the posterior palate. Meox2 plays role in fusion of the posterior palate.

Figure 4

At E13.5, the anterior palatal shelves first flip up to orient vertically when the posterior palatal shelves are still lying horizontal to each other (A). At E14, the posterior palatal shelves follow the anterior palatal shelves in orienting vertically, whereas the anterior palates begin to grow vertically toward each other to make contact (B). At E15, the anterior palatal shelves have made contact and fused, whereas the posterior shelves grow vertically (C). At E15.5, both the anterior and posterior palates have fused (D). At E16, the fusion between the primary and secondary palate occurs at the future secondary choana (E). Palatal shelves are divided into anterior (pink) Msx1 and posterior (aqua) Barx1 expression domains (A–E) representing future hard and soft palate, respectively. Fgf-Bmp gradients/thresholds maintain proper palatal growth and fusion through proliferation. Anterior Fgf10 and Bmps control proliferation via Shh expression. This directs anterior palate flip up and vertical growth at E13.5–E14 (A,B). Anterior Fgf-Bmp gradients along with posterior Fgf8 regulate proliferation and growth via Barx1 in the posterior palate at E14–E15 (B,C). Fusion is initiated at the anterior palate by Tgf-β3 through its receptor (C). Then the fusion extends posteriorly through Tgf-β-Meox2 (D). The fusion between the primary and secondary palate marks the completion of palatal fusion at E16 (D,E), via Bmpr1a mediated Shox2 and Tgf β signaling through its receptors.