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Review
. 2020 Nov;112(19):1588-1634.
doi: 10.1002/bdr2.1754. Epub 2020 Jul 15.

Genetics and signaling mechanisms of orofacial clefts

Kurt Reynolds  1   2   3 , Shuwen Zhang  1   2 , Bo Sun  1   2 , Michael A Garland  1   2 , Yu Ji  1   2   3 , Chengji J Zhou  1   2   3
Affiliations
Review

Genetics and signaling mechanisms of orofacial clefts

Kurt Reynolds et al. Birth Defects Res. 2020 Nov.

Abstract

Craniofacial development involves several complex tissue movements including several fusion processes to form the frontonasal and maxillary structures, including the upper lip and palate. Each of these movements are controlled by many different factors that are tightly regulated by several integral morphogenetic signaling pathways. Subject to both genetic and environmental influences, interruption at nearly any stage can disrupt lip, nasal, or palate fusion and result in a cleft. Here, we discuss many of the genetic risk factors that may contribute to the presentation of orofacial clefts in patients, and several of the key signaling pathways and underlying cellular mechanisms that control lip and palate formation, as identified primarily through investigating equivalent processes in animal models, are examined.

Keywords: Bmp/Tgfb signaling; Fgf signaling; Shh signaling; Wnt signaling; cleft lip/palate; human genetics; mouse models; retinoic acid signaling; signaling crosstalk; syndromic/non-syndromic.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.. Bmp/Tgf-β signaling and OFCs.
The canonical Tgf-β and Bmp pathways with OFC phenotypes of the signaling molecules demonstrated in mutant mouse models in red. clp, cleft lip/palate; cp, cleft palate.
Figure 2.
Figure 2.. Fgf signaling and OFCs.
The Fgf signaling and regulatory molecules associated with OFCs in mutant mouse models are listed in red.
Figure 3.
Figure 3.. RA signaling and OFCs.
The retinoid signaling and metabolic pathway components associated with OFCs demonstrated in mouse models are listed in red. cp, cleft palate.
Figure 4.
Figure 4.. Shh signaling and OFCs.
The OFC phenotypes of the Shh signaling molecules (in red font) which have been demonstrated in mutant mouse models. Cyclopamine and Vismodegib are teratogens that inhibit Shh signaling and can induce OFCs in mouse embryos. clp, cleft lip/palate; cp, cleft palate.
Figure 5.
Figure 5.. Wnt signaling and OFCs.
Wnt signaling pathways with components in which OFC phenotypes have been demonstrated in mutant mouse models listed in red. clp, cleft lip/palate; cp, cleft palate; mcl, median cleft lip.
See this image and copyright information in PMC

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