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.
Highlights
The development of specialized organs in vertebrates is tightly linked to the regulation of cell growth, apical-basal cell polarity and cell-cell adhesion during embryogenesis
The Dlgh-1 protein levels were reduced by approximately 50% in the Dlgh-1+/2 mice compared to the Dlgh1+/+ mice and Dlgh-1 protein was not detected in any of the tissues analyzed from the Dlgh-12/2 mice or in mouse embryo fibroblasts (MEFs) derived from day E14.5 Dlgh-1 null embryos (Fig. 1C)
The membrane-associated guanylate kinase (MAGUK) protein Dlgh-1, which is highly conserved crossspecies, has emerged as an important factor in the regulation of cell-cell adhesion, apical-basal polarity, and cell proliferation in Drosophila [1,2]. The regulation of these cellular aspects is critical for the establishment of specialized organs during embryogenesis
Summary
The development of specialized organs in vertebrates is tightly linked to the regulation of cell growth, apical-basal cell polarity and cell-cell adhesion during embryogenesis. The directed movements of cells and their orientation in the same direction within the plane of a tissue, termed planar cell polarity (PCP), appear to be crucial for the proper formation of the body plan. From studies in invertebrates it is known that certain PSD95/Dlg/ZO-1 (PDZ) domain containing proteins such as Discs-large (Dlg) play prominent roles in regulating apical-basal polarity [1,2] while different PDZ proteins are part of a genetic network that regulates PCP [3]. Studies suggest that certain factors have different or additional roles in vertebrates as compared to invertebrates [4].
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