Requirement for Dlgh-1 in Planar Cell Polarity and Skeletogenesis during Vertebrate Development

Abstract

The development of specialized organs is tightly linked to the regulation of cell growth, orientation, migration and adhesion during embryogenesis. In addition, the directed movements of cells and their orientation within the plane of a tissue, termed planar cell polarity (PCP), appear to be crucial for the proper formation of the body plan. In Drosophila embryogenesis, Discs large (dlg) plays a critical role in apical-basal cell polarity, cell adhesion and cell proliferation. Craniofacial defects in mice carrying an insertional mutation in Dlgh-1 suggest that Dlgh-1 is required for vertebrate development. To determine what roles Dlgh-1 plays in vertebrate development, we generated mice carrying a null mutation in Dlgh-1. We found that deletion of Dlgh-1 caused open eyelids, open neural tube, and misorientation of cochlear hair cell stereociliary bundles, indicative of defects in planar cell polarity (PCP). Deletion of Dlgh-1 also caused skeletal defects throughout the embryo. These findings identify novel roles for Dlgh-1 in vertebrates that differ from its well-characterized roles in invertebrates and suggest that the Dlgh-1 null mouse may be a useful animal model to study certain human congenital birth defects.

Common variants in DLG1 locus are associated with non‐syndromic cleft lip with or without cleft palate

“…[26][27][28] It has been shown that the loss of Dlg1 may affect craniofacial development through the disruption of WNT/planar cell polarity (PCP) signalling, which is involved in the process of dynamic tissue movement during organogenesis known as convergent extension. 28,29 It is worth noting that another important regulator of Wnt/PCP signalling is Wnt5a, which deficiency in mice leads to complete clefting of the secondary palate due to inhibition of the directional migration of cells required for palate formation. 30,31 Interstitial deletions of 3q29 in humans have recently been described as a new microdeletion syndrome.…”

The Scribble–Dlg–Lgl Module in Cell Polarity Regulation

“…In contrast to other family members, Dlg1 (SAP97) mutant mice are neonatal lethal, displaying craniofacial defects and kidney, urogenital, and lens development defects (Caruana and Bernstein 2001;Naim et al 2005;Mahoney et al 2006;Iizuka-Kogo et al 2007;Rivera et al 2009). More recently, Dlg1 null mice were shown to also display defects in skeletogenesis of the trunk and limb structures and, importantly, similarly to loss of Scribble, defects in neural tube, eyelid closure, and in the disorganization of the stereociliary bundles in the cochlea (Rivera et al 2013). These studies indicate a novel role for Dlg1 in PCP signaling.…”

Cell Polarity 1

“…In Drosophila, Scribble physically and genetically interacts with Vangl2 to direct PCP processes in the eye and the wing , and similar interactions have been found between Scribble and Vangl2 in zebrafish in the control of the PCP-mediated convergence extension movements during gastrulation (Wada et al 2005). Recent analysis of Dlg1 and Dlg3 knockout mice has also implicated mammalian Dlg in planar cell polarity regulation with both of these mice displaying at low penetrance the PCP mutant phenotypes, namely, cochlear hair cell misorientation and neural tube closure defects (Rivera et al 2013;Van Campenhout et al 2011). Finally, Lgl can bind to the PCP protein Dsh, which regulates Lgl localization, in both Drosophila epithelium and Xenopus tissues (Dollar et al 2005).…”

“…In contrast to other family members, Dlg1 (SAP97) mutant mice are neonatal lethal, displaying craniofacial defects and kidney, urogenital, and lens development defects (Caruana and Bernstein 2001;Naim et al 2005;Mahoney et al 2006;Iizuka-Kogo et al 2007;Rivera et al 2009). More recently, Dlg1 null mice were shown to also display defects in skeletogenesis of the trunk and limb structures and, importantly, similarly to loss of Scribble, defects in neural tube, eyelid closure, and in the disorganization of the stereociliary bundles in the cochlea (Rivera et al 2013). These studies indicate a novel role for Dlg1 in PCP signaling.…”