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The Role of Insulin Receptor Signaling in Zebrafish Embryogenesis

Division of Endocrinology, Diabetes, and Bone Diseases (Y.T., Y.W., S.Y., D.L.), Department of Medicine, and Department of Medicine-Division of Liver Disease and Department of Developmental and Regenerative Biology (C.M., C.G., K.C.S.), Mount Sinai School of Medicine, New York, New York 10029; and Molecular, Cellular, and Developmental Biology (C.D.), University of Michigan, Ann Arbor, Michigan 48105

Address all correspondence and requests for reprints to: Derek LeRoith, M.D., Ph.D, Chief, Division of Endocrinology, Diabetes, and Bone Disease, Department of Medicine, One Gustave L. Levy Place, Atran 4th Floor-36, Box 1055, New York, New York 10029-6574. E-mail: derek.leroith{at}mssm.edu.

Insulin receptor (IR) signaling is considered to be important in growth and development in addition to its major role in metabolic homeostasis. The metabolic role of insulin in carbohydrate and lipid metabolism is extensively studied. In contrast, the role of IR activation during embryogenesis is less understood. To address this, we examined the function of the IR during zebrafish development. Zebrafish express two isoforms of IR (insra and insrb). Both isoforms were cloned and show high homology to the human insulin receptor and can functionally substitute for the human IR in fibroblasts derived from insr gene-deleted mice. Gene expression studies reveal that these receptors are expressed at moderate levels in the central nervous system during development. Morpholino-mediated selective knockdown of each of the IR isoforms causes growth retardation and profound morphogenetic defects in the brain and eye. These results clearly demonstrate that IR signaling plays essential roles in vertebrate embryogenesis and growth.

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