**A Review of Orofacial Clefting and Current Genetic Mouse Models A Review of Orofacial Clefting and Current Genetic Mouse Models**

Aram J. Keteyian and Yuji Mishina Aram J. Keteyian and Yuji Mishina Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67052

#### **Abstract**

The prevalence of orofacial clefts (OFCs) is nearly 10.2 per 10,000 births in the United States and 9.9 per 10,000 births worldwide. OFCs occur as a result of a break (nonfusion) of orofacial structures during development. This can occur due to a variety of reasons;prenatal exposure to many drugs and environmental factors as well as genetic factors which are implicated in the development of OFCs. While approximately 15 types of clefts have been identified, there are at least four distinct classifications of OFCs. These include complete cleft palate with cleft lip; cleft of the anterior palate, which may/may not involve cleft lip; cleft of the posterior palate; and submucosal cleft. A number of candidate genes have been identified, including transforming growth factor beta (TGFβ) and homeobox genes (e.g., *MSX1*), among many others. What follows is a review of mouse models currently used in research and the classification of their overall contribution to known OFCs.

**Keywords:** orofacial, cleft lip, cleft palate, genomic, genetics, TGFβ, MSX1, knockout mice, craniofacial, molecular, palatogenesis

## **1. Introduction**

The focus of this chapter is to review a comprehensive list of the genes with known involvement in generating cleft lip with (or without) cleft palate (CL/P) or cleft palate (CP) in mice. Additionally, the associated knockout (KO) and conditional knockout (cKO) models are discussed. Most of the research models currently in use focus on complete CP, and thus not as much is known of the other CP phenotypes. In particular, identifying specific risk genes for CL/P is made simpler when genomic sequencing is done, and clefting associated with syndromes (syndromic) has identified single genetic loci that are involved with abnormalities in palatogenesis. Current mouse models involve a somewhat surprisingly vast array of genes, however, including *Wnt*, *Msx1/2*, *Tbx*, *Pax9*, *Irf6*, *Tgfb*, and *Fgf*. Further elucidation and

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

categorization of these gene families and their associated defects—whether syndromic or non-syndromic—can aid us in further clarifying the molecular mechanisms underlying orofacial clefting and potentially lead us to targeted, more efficient treatments.

We currently utilize four distinct classifications for OFCs: complete cleft palate with cleft lip; cleft of the anterior palate, which may/may not involve cleft lip; cleft of the posterior palate; and submucosal cleft. Subdivided among these four classifications of OFCs are six categories of developmental defects that have been shown to result in cleft palate in KO or cKO mice. The numerous variants of CL/P can generally be found to fit within one of the following categories: [1]


Each of the known KO/cKO mice mentioned is bred such that the gene missing is one already known to play a role in the development of CL/P. Implicit within these categories are the KO genes known to lead to each particular type of defect, each of which will be outlined as we move through this chapter.

As we look into the future, OFCs need to be classified with more definitive nomenclature. Currently, we use arbitrary terms to define very broadly into which category these congenital malformations fall, i.e., syndromic versus non-syndromic. As studies are broadened to include a wider array of genetic variants and their regulatory regions, more risk genes for CL/P and CP will surely be identified. As a result, more specific phenotypic classifications will emerge as well. The etiology of OFCs is complex, and the presentation is wide ranging; it is important that we continue to use precise genetic mouse models in order to carefully define a given phenotype before reclassifying human cases. The models mentioned in this chapter and those developed in the future are critical to a more sophisticated understanding of OFC anomalies and etiologic variants. Their development and utilization will ideally lead to a greater breadth and depth of treatment intervention options for patients.
