Molecular and Cellular Mechanisms of Palate Development

Abstract

Development of the mammalian secondary palate involves highly dynamic morphogenetic processes, including outgrowth of palatal shelves from the oral side of the embryonic maxillary prominences, elevation of the initially vertically oriented palatal shelves to the horizontal position above the embryonic tongue, and subsequently adhesion and fusion of the paired palatal shelves at the midline to separate the oral cavity from the nasal cavity. Perturbation of any of these processes could cause cleft palate, a common birth defect that significantly affects patients' quality of life even after surgical treatment. In addition to identifying a large number of genes required for palate development, recent studies have begun to unravel the extensive cross-regulation of multiple signaling pathways, including Sonic hedgehog, bone morphogenetic protein, fibroblast growth factor, transforming growth factor β, and Wnt signaling, and multiple transcription factors during palatal shelf growth and patterning. Multiple studies also provide new insights into the gene regulatory networks and/or dynamic cellular processes underlying palatal shelf elevation, adhesion, and fusion. Here we summarize major recent advances and integrate the genes and molecular pathways with the cellular and morphogenetic processes of palatal shelf growth, patterning, elevation, adhesion, and fusion.

Keywords: cell signaling; cleft palate; growth factor; growth/development; morphogenesis; transcription factor.

Figure 1.

Stages of mouse palate development. (A–C) Representative hematoxylin and eosin (HE)–stained coronal sections through the middle of the anterior-posterior axis of the developing palatal shelves at E13.5 (A), E14.0 (B), and E14.5 (C). p, palatal shelf; t, tongue. Dashed box in C marks the region shown in higher magnification in D. (D, E) Higher magnification views of HE-stained coronal sections through the middle of the palatal shelves undergoing fusion at E14.5 (D) and E15.5 (E). Arrows in D point to the epithelial triangles formed from displacement of epithelial cells in the oronasal axis during formation of the midline epithelial seam (MES). Arrowhead in D points to the single cell layer MES at the midline. Arrows in E point to epithelial islands during MES dissolution. Scale bars: 100 µm.

Figure 2.

Molecular regulation of palatal shelf growth and patterning. (A) Sonic hedgehog (Shh) is a central node in the signaling networks regulating palatal shelf growth and patterning throughout the anterior-posterior axis. (B, C) Molecular pathways specific for regulating growth in the anterior and posterior regions of the palatal shelf, respectively. Arrows represent inductive relationships, and blunt arrows indicate inhibition. epi, epithelium; mes, mesenchyme.

Figure 3.

Schematic representation of patterns of expression of several extracellular matrix molecules in the mid-posterior region of the palatal shelves before and after palatal shelf elevation. (A, B) The lateral and medial sides of the vertically oriented palatal shelf before elevation (A) correspond to the oral and nasal sides of the horizontally oriented palatal shelf (B) after elevation. Arrows in A indicate alignment of F-actin fibers toward the medial wall prior to shelf elevation. No actin fiber is depicted in B because the palatal mesenchyme cells in already elevated palatal shelves have less organized actin network (Chiquet et al. 2016).

Figure 4.

Molecular and cellular mechanisms of palatal adhesion and fusion. (A) Tgfβ3 signaling acts through multiple intracellular pathways and transcription factors in the medial edge epithelial (MEE) and overlying periderm to induce cell cycle exit, disrupt epithelial adhesion, and break down extracellular matrix (ECM). (B) Rho-kinase (ROCK)- and myosin light-chain kinase (MLCK)-activated nonmuscle myosin II (NMII)–mediated actomyosin contractility drives MEE cell intercalation, displacement, and extrusion during midline epithelial seam formation and breakdown. epi, epithelium; mes, mesenchyme.