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Fibronectin and integrin alpha 5 play essential roles in the development of the cardiac neural crest.

ABSTRACT: Cardiac neural crest (CNC) plays a requisite role during cardiovascular development and defects in the formation of CNC-derived structures underlie several common forms of human congenital birth defects. Migration of the CNC cells to their destinations as well as expansion and maintenance of these cells are important for the normal development of the cardiac outflow tract and aortic arch arteries; however, molecular mechanisms regulating these processes are not well-understood. Fibronectin (FN) protein is present along neural crest migration paths and neural crest cells migrate when plated on FN in vitro; therefore, we tested the role of FN during the development of the CNC in vivo. Our analysis of the fate of the neural crest shows that CNC cells reach their destinations in the branchial arches and the cardiac outflow tract in the absence of FN or its cellular receptor integrin ?5?1. However, we found that FN and integrin ?5 modulate CNC proliferation and survival, and are required for the presence of normal numbers of CNC cells at their destinations.

SUBMITTER: Mittal A

PROVIDER: S-EPMC3233353 | biostudies-literature | 2010 Sep-Dec

REPOSITORIES: biostudies-literature

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Fibronectin and integrin alpha 5 play essential roles in the development of the cardiac neural crest.

Mittal Ashok A Pulina Maria M Hou Shuan-Yu SY Astrof Sophie S

Mechanisms of development 20100831 9-12

Cardiac neural crest (CNC) plays a requisite role during cardiovascular development and defects in the formation of CNC-derived structures underlie several common forms of human congenital birth defects. Migration of the CNC cells to their destinations as well as expansion and maintenance of these cells are important for the normal development of the cardiac outflow tract and aortic arch arteries; however, molecular mechanisms regulating these processes are not well-understood. Fibronectin (FN) ...[more]

PMID: 20807571

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Project description:AimsThe adapter protein p130Cas, encoded by the Bcar1 gene, is a key regulator of cell movement, adhesion, and cell cycle control in diverse cell types. Bcar1 constitutive knockout mice are embryonic lethal by embryonic days (E) 11.5-12.5, but the role of Bcar1 in embryonic development remains unclear. Here, we investigated the role of Bcar1 specifically in cardiovascular development and defined the cellular and molecular mechanisms disrupted following targeted Bcar1 deletions.Methods and resultsWe crossed Bcar1 floxed mice with Cre transgenic lines allowing for cell-specific knockout either in smooth muscle and early cardiac tissues (SM22-Cre), mature smooth muscle cells (smMHC-Cre), endothelial cells (Tie2-Cre), second heart field cells (Mef2c-Cre), or neural crest cells (NCC) (Pax3-Cre) and characterized these conditional knock outs using a combination of histological and molecular biology techniques. Conditional knockout of Bcar1 in SM22-expressing smooth muscle cells and cardiac tissues (Bcar1SM22KO) was embryonically lethal from E14.5-15.5 due to severe cardiovascular defects, including abnormal ventricular development and failure of outflow tract (OFT) septation leading to a single outflow vessel reminiscent of persistent truncus arteriosus. SM22-restricted loss of Bcar1 was associated with failure of OFT cushion cells to undergo differentiation to septal mesenchymal cells positive for SMC-specific α-actin, and disrupted expression of proteins and transcription factors involved in epithelial-to-mesenchymal transformation (EMT). Furthermore, knockout of Bcar1 specifically in NCC (Bcar1PAX3KO) recapitulated part of the OFT septation and aortic sac defects seen in the Bcar1SM22KO mutants, indicating a cell-specific requirement for Bcar1 in NCC essential for OFT septation. In contrast, conditional knockouts of Bcar1 in differentiated smooth muscle, endothelial cells, and second heart field cells survived to term and were phenotypically normal at birth and postnatally.ConclusionOur work reveals a cell-specific requirement for Bcar1 in NCC, early myogenic and cardiac cells, essential for OFT septation, myocardialization and EMT/cell cycle regulation and differentiation to myogenic lineages.

Dataset Information

Fibronectin and integrin alpha 5 play essential roles in the development of the cardiac neural crest.

Publications

Fibronectin and integrin alpha 5 play essential roles in the development of the cardiac neural crest.

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