Mechanisms of palatal epithelial seam disintegration by transforming growth factor (TGF) β3

Abstract

TGFbeta3 signaling initiates and completes sequential phases of cellular differentiation that is required for complete disintegration of the palatal medial edge seam, that progresses between 14 and 17 embryonic days in the murine system, which is necessary in establishing confluence of the palatal stroma. Understanding the cellular mechanism of palatal MES disintegration in response to TGFbeta3 signaling will result in new approaches to defining the causes of cleft palate and other facial clefts that may result from failure of seam disintegration. We have isolated MES primary cells to study the details of MES disintegration mechanism by TGFbeta3 during palate development using several biochemical and genetic approaches. Our results demonstrate a novel mechanism of MES disintegration where MES, independently yet sequentially, undergoes cell cycle arrest, cell migration and apoptosis to generate immaculate palatal confluency during palatogenesis in response to robust TGFbeta3 signaling. The results contribute to a missing fundamental element to our base knowledge of the diverse roles of TGFbeta3 in functional and morphological changes that MES undergo during palatal seam disintegration. We believe that our findings will lead to more effective treatment of facial clefting.

Occurrence of Cleft-Palate and Alteration of <i>Tgf-</i>β_<i>3</i> Expression and the Mechanisms Leading to Palatal Fusion in Mice following Dietary Folic-Acid Deficiency

“…This normalization included an increase in MEE cell proliferation and a decrease in MES cell death, which have never been reported amongst the activities of TGF-␤ 3 [Murillo et al, 2009;Del Río et al, 2010]. Therefore, during palate development, TGF-␤ 3 , far from only inducing opposing MEE adhesion [Gato et al, 2002;Martínez-Sanz et al, 2008], MES cell death [Martínez-Álvarez et al, 2000b;Murillo et al, 2009] and epithelial-mesenchymal transformation [Ahmed et al, 2007], also appears to be an important regulatory agent of the mechanisms causing palatal fusion.…”

Nicotine Exposure During Pregnancy Results in Persistent Midline Epithelial Seam With Improper Palatal Fusion

“…These, in parallel with the transcription factors Snai1 and Snai2, promote MES apoptosis and disintegration. 6,21,[39][40][41][42][43] Our results demonstrated that not only the Tgfβ-pathway genes but also other pathway-related genes might interact each other to regulate medial edge epithelium disintegration and complete palatogenesis (Supplementary Figure 2) In several studies, it has been suggested that there is a gene-environment interaction exists between smoking and TGFα expression for the induction of cleft palate. 8,25,[44][45][46][47][48][49] By using our microarray analysis and filtering cleft palate-related genes, we determined that nicotine is the highly susceptible element of smoking to induce down-regulation of TGFα, which may explain the palatal size abnormality observed in nicotine-treated pups.…”

tgfβ3 regulation of chondrogenesis and osteogenesis in zebrafish is mediated through formation and survival of a subpopulation of the cranial neural crest

“…In mice, Tgfb3 is involved in mediating palatal fusion via repressing E-cadherin transcription, leading to epithelial mesenchymal transformation (EMT) and cell migration (Dudas et al, 2004;Nawshad and Hay, 2003;Nawshad et al, 2007). Under the influence of Tgfb3, the murine palatal MEE cells undergo cell cycle arrest, cell migration and apoptosis to generate palatal confluency (Ahmed et al, 2007). In comparison, our data shows that the role of zebrafish tgfb3 in palatogenesis differs from murine Tgfb3.…”

“…Lef1 in turn binds to the E-cadherin promoter and represses its transcription, leading to epithelial mesenchymal transformation (EMT) and cell migration . Furthermore, MEE cells isolated from mice can chronologically undergo cell cycle arrest, cell migration and apoptosis to generate palatal confluency in response to TGFb3 treatment (Ahmed et al, 2007).…”