Requirement of DLG1 for cardiovascular development and tissue elongation during cochlear, enteric, and skeletal development: possible role in convergent extension.

Akiko Iizuka-Kogo,Nobuhiko Sawai,Tetsu Akiyama,Takao Senda,Hiroshi Kogo,Yoshimi Hasegawa,Ken-Ichi Yamamura,Toshiyuki Matsuzaki,Ryuji Nomura,Atsushi Shimomura,Ben Hogan

doi:10.1371/journal.pone.0123965

Akiko Iizuka-Kogo, Nobuhiko Sawai + Show 9 more

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https://doi.org/10.1371/journal.pone.0123965

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Abstract

The Dlg1 gene encodes a member of the MAGUK protein family involved in the polarization of epithelial cells. Null mutant mice for the Dlg1 gene (Dlg1-/- mice) exhibit respiratory failure and cyanosis, and die soon after birth. However, the cause of this neonatal lethality has not been determined. In the present study, we further examined Dlg1-/- mice and found severe defects in the cardiovascular system, including ventricular septal defect, persistent truncus arteriosus, and double outlet right ventricle, which would cause the neonatal lethality. These cardiovascular phenotypes resemble those of mutant mice lacking planar cell polarity (PCP) genes and support a recent notion that DLG1 is involved in the PCP pathway. We assessed the degree of involvement of DLG1 in the development of other organs, as the cochlea, intestine, and skeleton, in which PCP signaling has been suggested to play a role. In the organ of Corti, tissue elongation was inhibited accompanied by disorganized arrangement of the hair cell rows, while the orientation of the stereocilia bundle was normal. In the sternum, cleft sternum, abnormal calcification pattern of cartilage, and disorganization of chondrocytes were observed. Furthermore, shortening of the intestine, sternum, and long bones of the limbs was observed. These phenotypes of Dlg1-/- mice involving cellular disorganization and insufficient tissue elongation strongly suggest a defect in the convergent extension movements in these mice. Thus, our present results provide a possibility that DLG1 is particularly required for convergent extension among PCP signaling-dependent processes.

Highlights

In multicellular organisms, two subcellular compartments in single cells often become differently specialized in structure and function according to the tissue functions
Because Dlg1-/- infant mice exhibit respiratory failure and cyanosis, we suspected a defect in the cardiovascular system and examined the gross anatomy of the heart outflow tract in Dlg1-/- mice at E18.5
In Dlg1-/- mice, malposition of the great arteries, in which the pulmonary artery and the aorta were parallel (Fig 1B) rather than crossing as they did in control mice (Fig 1A), and a single outflow tract indicating persistent truncus arteriosus (PTA) (Fig 1C) were observed (Table 1)

Summary

Introduction

Two subcellular compartments in single cells often become differently specialized in structure and function according to the tissue functions. This organization of subcellular components and structures is known as cellular polarization [1]. The PCP signaling pathway is required for the above-mentioned planar cell polarization, and for dynamic tissue movement during organogenesis [4]. This tissue movement is called convergent extension (CE). The extents of the dependence of these phenotypes on PCP or CE remain to be elucidated

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