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Persistent Expression of Notch2 Delays Gonadotrope Differentiation

Department of Human Genetics (L.T.R., B.S.W., S.A.C.), University of Michigan, Ann Arbor, Michigan 48109-0638; Murdoch Children’s Research Institute (S.A.R., P.Q.T.), Royal Children’s Hospital, Melbourne, Victoria 3052, Australia; and Department of Paediatrics (P.Q.T.), University of Melbourne, Victoria 3010, Australia

Address all correspondence and requests for reprints to: Sally A. Camper, 4909 Buhl Building. Ann Arbor, Michigan 48109-0618. E-mail: scamper{at}umich.edu.

Normal pituitary gland development requires coordination between maintenance of progenitor cell pools and selection of progenitors for differentiation. The spatial and temporal expression of Notch2 during pituitary development suggested that it could control progenitor cell differentiation in the pituitary. Consistent with this idea, Notch2 is not expressed in Prop1 mutants, and anterior pituitary progenitors in Prop1 mutants appear to be unable to transition from proliferation to differentiation properly, resulting in anterior lobe failed cell specification and evolving hypoplasia. To test the function of Notch2 directly, we used the GSU subunit promoter to express activated NOTCH2 persistently in pre-gonadotropes and pre-thyrotropes of transgenic mice. At birth, there is a small reduction in the population of fully differentiated thyrotropes and almost no fully differentiated gonadotropes. The temporal and spatial expression of Hey1 suggests that it could be a mediator of this effect. Gonadotropes complete their differentiation program eventually, although expression of LH and FSH is mutually exclusive with NOTCH2 transgene expression. This demonstrates that activated Notch2 is sufficient to delay gonadotrope differentiation, and it supports the hypothesis that Notch2 regulates progenitor cell differentiation in the pituitary gland.

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