Development of Normal and Cleft Palate: A Central Role for Connective Tissue Growth Factor (CTGF)/CCN2

Abstract

Development of the palate is the result of an organized series of events that require exquisite spatial and temporal regulation at the cellular level. There are a myriad of growth factors, receptors and signaling pathways that have been shown to play an important role in growth, elevation and/or fusion of the palatal shelves. Altered expression or activation of a number of these factors, receptors and signaling pathways have been shown to cause cleft palate in humans or mice with varying degrees of penetrance. This review will focus on connective tissue growth factor (CTGF) or CCN2, which was recently shown to play an essential role in formation of the secondary palate. Specifically, the absence of CCN2 in KO mice results in defective cellular processes that contribute to failure of palatal shelf growth, elevation and/or fusion. CCN2 is unique in that it has been shown to interact with a number of other factors important for palate development, including bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), epidermal growth factor (EGF), Wnt proteins and transforming growth factor-βs (TGF-βs), thereby influencing their ability to bind to their receptors and mediate intracellular signaling. The role that these factors play in palate development and their specific interactions with CCN2 will also be reviewed. Future studies to elucidate the precise mechanisms of action for CCN2 and its interactions with other regulatory proteins during palatogenesis are expected to provide novel information with the potential for development of new pharmacologic or genetic treatment strategies for clinical intervention of cleft palate during development.

Load Transfer during Magnetic Mucoperiosteal Distraction in Newborns with Complete Unilateral and Bilateral Orofacial Clefts: A Three-Dimensional Finite Element Analysis

“…A complete fusion failure results in a cleft of the lip through the vermillion border that extends to the nasal sill and in a cleft of the alveolar process [7]. The cleft of the secondary palate occurs at 8-12 weeks of gestation due to fusion failure of the palatal shelves of the maxillary processes [8,9] that results in a cleft in the palatal roof and soft palate that extends to the uvula.…”

An integrative, genomic, transcriptomic and network-assisted study to identify genes associated with human cleft lip with or without cleft palate

“…Existing studies about ErbB family mostly focus on its relationship with solid tumors or neurodegenerative diseases. Mice with a deficiency for Egfr, a member of the ErbB family, exhibit facial anomalies and impaired epithelial development through a failure of secretion of matrix metalloproteinases [35][36][37]. These studies may serve as genetic correlation evidence of ErbB family in human CL/P.…”

Extracellular Matrix Composition and Remodeling: Current Perspectives on Secondary Palate Formation, Cleft Lip/Palate, and Palatal Reconstruction

“…The actions of numerous morphogens in palatogenesis have been extensively studied, mainly secreted factors such as HH (Cobourne and Green, 2012;Dworkin et al, 2016;Xavier et al, 2016;, FGF (Jiang et al, 2006;Nie et al, 2006;Snyder-Warwick and Perlyn, 2012;Stanier and Pauws, 2012;Prochazkova et al, 2018;Weng et al, 2018), TGF-β (Nawshad et al, 2004;Iwata et al, 2011;Nakajima et al, 2018), BMP (Nie et al, 2006;Parada and Chai, 2012;Graf et al, 2016), and Wnt/β-catenin family proteins (He and Chen, 2012), which are responsible for guiding all steps of palate formation by reciprocal signaling between the embryonic oral epithelium and palatal mesenchyme, as well as transcription factor regulation (Greene and Pisano, 2010;Levi et al, 2011;Bush and Jiang, 2012;Li et al, 2017). Also, other morphogens and growth factors have emerged in palatogenesis, such as connective tissue growth factor (Tarr et al, 2018) and retinoic acid (Okano et al, 2014;Mammadova et al, 2016). Dysregulation of these pathways through genetic variations in individual genes has been suggested as strongly associated with CL/P (Pauws and Stanier, 2007;Krejci et al, 2009;Tang et al, 2013;Okano et al, 2014;Reynolds et al, 2019).…”