title: ISL1 Is Necessary for Maximal Thyrotrope Response to Hypothyroidism.
abstract: ISLET1 is a homeodomain transcription factor necessary for development of the pituitary, retina, motor neurons, heart, and pancreas. Isl1-deficient mice (Isl1(-/-)) die early during embryogenesis at embryonic day 10.5 due to heart defects, and at that time, they have an undersized pituitary primordium. ISL1 is expressed in differentiating pituitary cells in early embryogenesis. Here, we report the cell-specific expression of ISL1 and assessment of its role in gonadotropes and thyrotropes. Isl1 expression is elevated in pituitaries of Cga(-/-) mice, a model of hypothyroidism with thyrotrope hypertrophy and hyperplasia. Thyrotrope-specific disruption of Isl1 with Tshb-cre is permissive for normal serum TSH, but T4 levels are decreased, suggesting decreased thyrotrope function. Inducing hypothyroidism in normal mice causes a reduction in T4 levels and dramatically elevated TSH response, but mice with thyrotrope-specific disruption of Isl1 have a blunted TSH response. In contrast, deletion of Isl1 in gonadotropes with an Lhb-cre transgene has no obvious effect on gonadotrope function or fertility. These results show that ISL1 is necessary for maximal thyrotrope response to hypothyroidism, in addition to its role in development of Rathke's pouch.
authors: Human Genetics, University of Michigan (F.C., M.L.B., A.H.M., P.G., S.A.C.), Ann Arbor, Michigan 48109; Beth Israel Deaconess Medical Center (K.R.V., A.N.H.), Harvard University, Boston, Massachusetts 02215; Aix-Marseille University (F.C., T.B.), Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Centre National de la Recherche Scientifique, Faculté de Médecine de Marseille, and Assistance Publique-Hôpitaux de Marseille, Department of Endocrinology, Hôpital de la Timone, Marseille, France 13000; and University of Rochester School of Medicine and Dentistry (L.G.), Rochester, New York 14642.
authors: F
authors: F
authors: Castinetti
authors: Human Genetics, University of Michigan (F.C., M.L.B., A.H.M., P.G., S.A.C.), Ann Arbor, Michigan 48109; Beth Israel Deaconess Medical Center (K.R.V., A.N.H.), Harvard University, Boston, Massachusetts 02215; Aix-Marseille University (F.C., T.B.), Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Centre National de la Recherche Scientifique, Faculté de Médecine de Marseille, and Assistance Publique-Hôpitaux de Marseille, Department of Endocrinology, Hôpital de la Timone, Marseille, France 13000; and University of Rochester School of Medicine and Dentistry (L.G.), Rochester, New York 14642.
authors: M L
authors: ML
authors: Brinkmeier
authors: Human Genetics, University of Michigan (F.C., M.L.B., A.H.M., P.G., S.A.C.), Ann Arbor, Michigan 48109; Beth Israel Deaconess Medical Center (K.R.V., A.N.H.), Harvard University, Boston, Massachusetts 02215; Aix-Marseille University (F.C., T.B.), Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Centre National de la Recherche Scientifique, Faculté de Médecine de Marseille, and Assistance Publique-Hôpitaux de Marseille, Department of Endocrinology, Hôpital de la Timone, Marseille, France 13000; and University of Rochester School of Medicine and Dentistry (L.G.), Rochester, New York 14642.
authors: A H
authors: AH
authors: Mortensen
authors: Human Genetics, University of Michigan (F.C., M.L.B., A.H.M., P.G., S.A.C.), Ann Arbor, Michigan 48109; Beth Israel Deaconess Medical Center (K.R.V., A.N.H.), Harvard University, Boston, Massachusetts 02215; Aix-Marseille University (F.C., T.B.), Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Centre National de la Recherche Scientifique, Faculté de Médecine de Marseille, and Assistance Publique-Hôpitaux de Marseille, Department of Endocrinology, Hôpital de la Timone, Marseille, France 13000; and University of Rochester School of Medicine and Dentistry (L.G.), Rochester, New York 14642.
authors: K R
authors: KR
authors: Vella
authors: Human Genetics, University of Michigan (F.C., M.L.B., A.H.M., P.G., S.A.C.), Ann Arbor, Michigan 48109; Beth Israel Deaconess Medical Center (K.R.V., A.N.H.), Harvard University, Boston, Massachusetts 02215; Aix-Marseille University (F.C., T.B.), Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Centre National de la Recherche Scientifique, Faculté de Médecine de Marseille, and Assistance Publique-Hôpitaux de Marseille, Department of Endocrinology, Hôpital de la Timone, Marseille, France 13000; and University of Rochester School of Medicine and Dentistry (L.G.), Rochester, New York 14642.
authors: P
authors: P
authors: Gergics
authors: Human Genetics, University of Michigan (F.C., M.L.B., A.H.M., P.G., S.A.C.), Ann Arbor, Michigan 48109; Beth Israel Deaconess Medical Center (K.R.V., A.N.H.), Harvard University, Boston, Massachusetts 02215; Aix-Marseille University (F.C., T.B.), Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Centre National de la Recherche Scientifique, Faculté de Médecine de Marseille, and Assistance Publique-Hôpitaux de Marseille, Department of Endocrinology, Hôpital de la Timone, Marseille, France 13000; and University of Rochester School of Medicine and Dentistry (L.G.), Rochester, New York 14642.
authors: T
authors: T
authors: Brue
authors: Human Genetics, University of Michigan (F.C., M.L.B., A.H.M., P.G., S.A.C.), Ann Arbor, Michigan 48109; Beth Israel Deaconess Medical Center (K.R.V., A.N.H.), Harvard University, Boston, Massachusetts 02215; Aix-Marseille University (F.C., T.B.), Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Centre National de la Recherche Scientifique, Faculté de Médecine de Marseille, and Assistance Publique-Hôpitaux de Marseille, Department of Endocrinology, Hôpital de la Timone, Marseille, France 13000; and University of Rochester School of Medicine and Dentistry (L.G.), Rochester, New York 14642.
authors: A N
authors: AN
authors: Hollenberg
authors: Human Genetics, University of Michigan (F.C., M.L.B., A.H.M., P.G., S.A.C.), Ann Arbor, Michigan 48109; Beth Israel Deaconess Medical Center (K.R.V., A.N.H.), Harvard University, Boston, Massachusetts 02215; Aix-Marseille University (F.C., T.B.), Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Centre National de la Recherche Scientifique, Faculté de Médecine de Marseille, and Assistance Publique-Hôpitaux de Marseille, Department of Endocrinology, Hôpital de la Timone, Marseille, France 13000; and University of Rochester School of Medicine and Dentistry (L.G.), Rochester, New York 14642.
authors: L
authors: L
authors: Gan
authors: Human Genetics, University of Michigan (F.C., M.L.B., A.H.M., P.G., S.A.C.), Ann Arbor, Michigan 48109; Beth Israel Deaconess Medical Center (K.R.V., A.N.H.), Harvard University, Boston, Massachusetts 02215; Aix-Marseille University (F.C., T.B.), Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Centre National de la Recherche Scientifique, Faculté de Médecine de Marseille, and Assistance Publique-Hôpitaux de Marseille, Department of Endocrinology, Hôpital de la Timone, Marseille, France 13000; and University of Rochester School of Medicine and Dentistry (L.G.), Rochester, New York 14642.
authors: S A
authors: SA
authors: Camper
mesh_terms: D000818:Animals; D049628:Body Size; D017353:Gene Deletion; D052681:Gonadotrophs / Q000378:metabolism; D007037:Hypothyroidism / Q000378:metabolism*; D019426:Integrases / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000378:metabolism*; D018345:Mice, Knockout; D052684:Thyrotrophs / Q000378:metabolism*; D037322:Thyrotropin, beta Subunit / Q000378:metabolism; D050817:Transcription Factor Pit-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D019426:Integrases; D060850:LIM-Homeodomain Proteins; D037322:Thyrotropin, beta Subunit; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; C494185:Pou1f1 protein, mouse; C063843:insulin gene enhancer binding protein Isl-1; C045073:Cre recombinase