Cleft lip and palate genetics and application in early embryological development

Abstract

The development of the head involves the interaction of several cell populations and coordination of cell signalling pathways, which when disrupted can cause defects such as facial clefts. This review concentrates on genetic contributions to facial clefts with and without cleft palate (CP). An overview of early palatal development with emphasis on muscle and bone development is blended with the effects of environmental insults and known genetic mutations that impact human palatal development. An extensive table of known genes in syndromic and non-syndromic CP, with or without cleft lip (CL), is provided. We have also included some genes that have been identified in environmental risk factors for CP/L. We include primary and review references on this topic.

Figure 1

Schematic drawing showing coronal view of a normal palate shelf and key stages of mouse palatal development. At E12-E13 days in the mouse gestation, the palatal shelves grow downward along the tongue (t). At E13-E13.5 days, the palatal shelves become elevated above the tongue. At E14.5, the palatal shelves adhere to each other in the midline. After E15.5 days, the MES completely degrades, and the palate fuses

Figure 2

Comparison of the morphogenesis of the upper lip (A-C) with that of the palate (D-F). After the bilateral maxillary processes (max) fuse externally with the inter-maxillary segment, the resulting epithelial seam (arrow, B) gives rise to mesenchyme (arrowhead, C) to produce a confluent lip. At a later time, the palatal shelves arising internally from the maxillary processes fuse with each other (arrows, D) and with the nasal septum (ns) above them, creating an epithelial seam that transforms to mesenchyme (arrowheads, E) to produce the confluent palate (arrowheads, F). p, sloughed periderm cells. Reprinted with permission.[44]

Figure 3

(A) Diagram showing the relationship between the NC cartilages and the transpalatal suture. Dotted lines indicate cut lines for removing the palate from the embryo and the NC cartilage from above the sutures. (B-E) Micrographs of parasagittal sections of foetal rat heads show the pre-natal development of TP sutures. (B) At E16, NC cartilages (arrows) can be seen directly above the presumptive TP suture region (in box). (C) High-power micrograph of the region in the box, showing the advancing palatal plate of the maxilla and horizontal plate of the palatal bone (asterisks) on either side of the presumptive TP suture (between arrows). (D) At E18, the advancing bone fronts (asterisks) begin to overlap one another, creating a highly cellular suture blastema (between arrows). (E) By E20, an elongated TP suture (between arrows) continues to form as the bone fronts proceed to overlap one another. A, airway; B, shelves of maxillary bones; MP, midpalatal suture; NCC, nasal capsular cartilage; O, oral cavity; TP, transpalatal suture. Reprinted with permission.[87]