RT Journal Article SR Electronic T1 Essential role of the Crk family-dosage in DiGeorge-like anomaly and metabolic homeostasis JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e201900635 DO 10.26508/lsa.201900635 VO 3 IS 2 A1 Akira Imamoto A1 Sewon Ki A1 Leiming Li A1 Kazunari Iwamoto A1 Venkat Maruthamuthu A1 John Devany A1 Ocean Lu A1 Tomomi Kanazawa A1 Suxiang Zhang A1 Takuji Yamada A1 Akiyoshi Hirayama A1 Shinji Fukuda A1 Yutaka Suzuki A1 Mariko Okada YR 2020 UL https://www.life-science-alliance.org/content/3/2/e201900635.abstract AB 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 2-deoxy-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.