Document Type

Article

Publication Date

2-2020

DOI

10.26508/lsa.201900635

Publication Title

Life Science Alliance

Volume

3

Issue

2

Pages

e201900635 (18 pp.)

Abstract

CRK and CRKL (CRK-like) encode adapter proteins with similar biochemical properties. Here, we show that a 50% reduction of the family-combined dosage generates developmental defects, including aspects of DiGeorge/del22q11 syndrome in mice. Like the mouse homologs of two 22q11.21 genes CRKL and TBX1, Crk and Tbx1 also genetically interact, thus suggesting that pathways shared by the three genes participate in organogenesis affected in the syndrome. We also show that Crk and Crkl are required during mesoderm development, and Crk/Crkl deficiency results in small cell size and abnormal mesenchyme behavior in primary embryonic fibroblasts. Our systems-wide analyses reveal impaired glycolysis, associated with low Hif1a protein levels as well as reduced histone H3K27 acetylation in several key glycolysis genes. Furthermore, Crk/Crkl deficiency sensitizes MEFs to 2deoxy-D-glucose, a competitive inhibitor of glycolysis, to induce cell blebbing. Activated Rapgef1, a Crk/Crkl-downstream effector, rescues several aspects of the cell phenotype, including proliferation, cell size, focal adhesions, and phosphorylation of p70 S6k1 and ribosomal protein S6. Our investigations demonstrate that Crk/Crkl-shared pathways orchestrate metabolic homeostasis and cell behavior through widespread epigenetic controls.

Comments

This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/ licenses/by/4.0/).

Original Publication Citation

Imamoto, A., Ki, S., Li, L., Iwamoto, K., Maruthamuthu, V., Devany, J., . . . Okada, M. (2020). Essential role of the Crk family-dosage in digeorge-like anomaly and metabolic homeostasis. Life Science Alliance, 3(2), e201900635. doi:10.26508/lsa.201900635

ORCID

0000-0002-3470-5274 (Maruthamuthu)

Download

Share

COinS