Extracellular Matrix in Secondary Palate Development

Abstract

The secondary palate arises from outgrowths of epithelia-covered embryonic mesenchyme that grow from the maxillary prominence, remodel to meet over the tongue, and fuse at the midline. These events require the coordination of cell proliferation, migration, and gene expression, all of which take place in the context of the extracellular matrix (ECM). Palatal cells generate their ECM, and then stiffen, degrade, or otherwise modify its properties to achieve the required cell movement and organization during palatogenesis. The ECM, in turn, acts on the cells through their matrix receptors to change their gene expression and thus their phenotype. The number of ECM-related gene mutations that cause cleft palate in mice and humans is a testament to the crucial role the matrix plays in palate development and a reminder that understanding that role is vital to our progress in treating palate deformities. This article will review the known ECM constituents at each stage of palatogenesis, the mechanisms of tissue reorganization and cell migration through the palatal ECM, the reciprocal relationship between the ECM and gene expression, and human syndromes with cleft palate that arise from mutations of ECM proteins and their regulators. Anat Rec, 303:1543Rec, 303: -1556Rec, 303: , 2020

Cellular and developmental basis of orofacial clefts

“…There are multiple types of intermediate filaments that may be composed of keratin, desmin, vimentin, lamin, and other proteins (Traub, 2012). The cytoskeletal network mostly associated with OFCs is comprised of microfilaments, which are the major force generating machinery of the cell (Logan, Ruest, Benson, & Svoboda, 2019; Svitkina, 2018). Along with microtubules, microfilaments form fibers that generate subcellular structures and link organelles, vesicles, and other components (Fletcher & Mullins, 2010).…”

“…Integrins facilitate adhesion and signaling between cells, and the various heterodimer combinations serve as receptors for ECM‐related proteins such as collagens, fibronectins, vitronectins, versican, osteopontin, tenascins, laminins, nephronectin, talin, and filamin (Barczyk, Carracedo, & Gullberg, 2010; Brandenberger et al, 2001; Denda, Reichardt, & Muller, 1998; Garcia‐Alvarez et al, 2003; Kiema et al, 2006; Y. J. Wu, La Pierre, Wu, Yee, & Yang, 2005; Yokosaki et al, 1998). Current models for palatogenesis rely on tight spatiotemporal control over both ECM and cytoskeletal dynamics, and mutations of certain ECM and cytoskeletal genes are linked with human OFCs (Logan et al, 2019).…”

“…Together, these studies demonstrate that glycoprotein and proteoglycan synthesis are indispensable for orofacial development in mammalian models. A recent review by Logan et al (2019) listed 67 ECM‐related genes that have been associated with human OFCs, among which are Collagen types II, IX, and XI (Logan et al, 2019). It is therefore important to understand the extracellular mechanisms that direct orofacial development and how alterations of these can lead to OFCs.…”

“…During embryogenesis or tissue regeneration, the ECM specializes to facilitate developmental processes such as growth factor signaling, tissue enlargement, and cell migration (Dutta & Dutta, 2010; Ramirez et al, 2007). In the palatal shelves, ECM proteins likely facilitate morphological changes by increasing shelf volume, directing force during elevation, serving as a scaffold for cytoskeletal contraction, and contributing to cell migration and tissue fusion (Logan et al, 2019). Secreted growth factors such as Tgf‐α, Tgf‐β3, and Bmp7 have been shown to control ECM protein expression during orofacial development (Kaartinen et al, 1997; Meng et al, 2009; Proetzel et al, 1995; Wyatt, Osborne, Stewart, & Ragge, 2010).…”

Extracellular matrix: The proteins that function throughout the body

“…The ECM includes secreted proteins that have very complicated biosynthetic pathways and, if disrupted, can cause stress in the cell organelles, especially the endoplasmic reticulum, so even non‐ECM proteins and factors can affect cellular function. Many of the ECM mutations reported in this article are reinforced in the review on the ECM role in palate development (Logan et al, 2020). The palate review covers the known ECM molecules in each stage of palatogenesis, and the mechanisms of tissue reorganization and cell migration through the ECM.…”