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Review
. 2020 Nov;112(19):1558-1587.
doi: 10.1002/bdr2.1768. Epub 2020 Jul 29.

Cellular and developmental basis of orofacial clefts

Yu Ji  1   2   3 , Michael A Garland  1   2 , Bo Sun  1   2 , Shuwen Zhang  1   2 , Kurt Reynolds  1   2   3 , Moira McMahon  2 , Ratheya Rajakumar  1   2 , Mohammad S Islam  2 , Yue Liu  2 , YiPing Chen  4 , Chengji J Zhou  1   2   3
Affiliations
Review

Cellular and developmental basis of orofacial clefts

Yu Ji et al. Birth Defects Res. 2020 Nov.

Abstract

During craniofacial development, defective growth and fusion of the upper lip and/or palate can cause orofacial clefts (OFCs), which are among the most common structural birth defects in humans. The developmental basis of OFCs includes morphogenesis of the upper lip, primary palate, secondary palate, and other orofacial structures, each consisting of diverse cell types originating from all three germ layers: the ectoderm, mesoderm, and endoderm. Cranial neural crest cells and orofacial epithelial cells are two major cell types that interact with various cell lineages and play key roles in orofacial development. The cellular basis of OFCs involves defective execution in any one or several of the following processes: neural crest induction, epithelial-mesenchymal transition, migration, proliferation, differentiation, apoptosis, primary cilia formation and its signaling transduction, epithelial seam formation and disappearance, periderm formation and peeling, convergence and extrusion of palatal epithelial seam cells, cell adhesion, cytoskeleton dynamics, and extracellular matrix function. The latest cellular and developmental findings may provide a basis for better understanding of the underlying genetic, epigenetic, environmental, and molecular mechanisms of OFCs.

Keywords: cell adhesion; cleft lip/palate; convergence and extrusion; cytoskeleton dynamics; epithelial seam; epithelial-mesenchymal transition; extracellular matrix; neural crest cells; periderm; primary cilia.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.. Illustrative diagrams for major types of orofacial clefts in humans.
(A) Normally fused orofacial structures. (B) Unilateral cleft lip (can be left or right with varied severities). (C) Bilateral cleft lip. (D) Unilateral cleft lip with cleft palate. (E) Bilateral cleft lip with cleft palate. (F) Cleft palate only. N, nose; P, palate; T, tongue; UP, upper lip.
Figure 2.
Figure 2.. Scanning electron microscopy of the upper lip morphogenesis in mouse embryos (modified from (L. Song et al., 2009)).
Front facial views show the key steps of the upper lip formation from E9.5 to E11.5. (A) The nasal placode (NP) can be identified by the formation of rich microvilli (not shown) on the surface at E9.5. (B) Following the formation and outgrowth of the medial nasal prominence (MNP) and lateral nasal prominence (LNP), the nasal pit (np) becomes evident at E10.5. The MNP and LNP merge ventrally and will fuse together with the maxillary prominence (MxP) at the lambdoidal (λ) junction (indicated by arrowheads). (C) At E11.5, the ventral MNP is widely connected and fused with both the LNP and the MxP, and the paired MNPs are dorsally attached at the facial midline.
Figure 3.
Figure 3.. Dynamic morphological changes during palatogenesis in mouse embryos.
Representative coronal sections stained by H&E demonstrate the key steps of palatogenesis, including the vertical growth of the palatal shelves (PS) alongside the tongue (T) at E13.5 (A), horizontal elevation and contact at the midline at E14.5 (B), the formation of medial epithelial seem (MES) at E15.0 (C), and the completion of palatal fusion at E16.5 (D).
Figure 4.
Figure 4.. Proliferation and apoptosis during lip fusion at E11.5 in mouse embryos (modified from (L. Song et al., 2009)).
(A) Immunohistochemistry demonstrates robust BrdU incorporation (red, indicating proliferation) in the majority of orofacial primordial cells, except the epithelial seem cells (arrow) at the fusion site. (B) TUNEL assay demonstrates the programmed cell death (green) of the epithelial seem at the fusion site (arrow). LNP, lateral nasal prominence; MNP, medial nasal prominence; np, nasal pit.
Figure 5.
Figure 5.. Illustrative diagram of the primary ciliary structure.
The primary cilium is a membrane-bound organelle that extends from the basal body (mother centriole). The axoneme of a primary ciliary contains nine doublet microtubules. The transition zone is localized at the proximal region of the cilium from the distal end of the basal body, defined by the presence of Y-links. The intraflagellar transport (IFT) system mediates the transport of ciliary cargos. The ciliary membrane (red) is enriched with receptors for signaling transduction. Several orofacial developmental signaling pathways that may act through the primary cilia are listed. Craniofacial ciliopathies with orofacial clefts that caused by disrupting the major ciliary components and associated genes are also listed.
See this image and copyright information in PMC

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