TY - JOUR T1 - Essential role of the <em>Crk</em> family-dosage in DiGeorge-like anomaly and metabolic homeostasis JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201900635 VL - 3 IS - 2 SP - e201900635 AU - Akira Imamoto AU - Sewon Ki AU - Leiming Li AU - Kazunari Iwamoto AU - Venkat Maruthamuthu AU - John Devany AU - Ocean Lu AU - Tomomi Kanazawa AU - Suxiang Zhang AU - Takuji Yamada AU - Akiyoshi Hirayama AU - Shinji Fukuda AU - Yutaka Suzuki AU - Mariko Okada Y1 - 2020/02/01 UR - https://www.life-science-alliance.org/content/3/2/e201900635.abstract N2 - 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. ER -