Title

Crk and Crkl have shared functions in neural crest cells for cardiac outflow tract septation and vascular smooth muscle differentiation.

Document Type

Article

Publication Date

4-22-2022

Identifier

DOI: 10.1093/hmg/ddab313

Abstract

CRK and CRKL encode cytoplasmic adaptors that contribute to the etiology of congenital heart disease. Neural crest cells (NCCs) are required for cardiac outflow tract (OFT) septation and aortic arch formation. The roles of Crk/Crkl in NCCs during mouse cardiovascular development remain unknown. To test this, we inactivated Crk and/or Crkl in NCCs. We found that the loss of Crk, rather than Crkl, in NCCs resulted in double outlet right ventricle, while loss of both Crk/Crkl in NCCs resulted in severe defects with earlier lethality due to failed OFT septation and severe dilation of the pharyngeal arch arteries (PAAs). We found that these defects are due to altered cell morphology resulting in reduced localization of NCCs to the OFT and failed integrity of the PAAs, along with reduced expression of Integrin signaling genes. Further, molecular studies identified reduced differentiation of vascular smooth muscle cells that may in part be due to altered Notch signaling. Additionally, there is increased cellular stress that leads to modest increase in apoptosis. Overall, this explains the mechanism for the Crk/Crkl phenotype.

Journal Title

Human molecular genetics

Volume

31

Issue

8

First Page

1197

Last Page

1215

MeSH Keywords

Animals; Cell Differentiation; Heart Defects, Congenital; Mice; Muscle, Smooth, Vascular; Neural Crest; Proto-Oncogene Proteins c-crk; Signal Transduction

Keywords

Cell Differentiation; Congenital Heart Defects; Vascular Smooth Muscle; Neural Crest; Proto-Oncogene Proteins c-crk; Signal Transduction

Comments

Grant support

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