Normal development of the pituitary gland requires coordination between the maintenance of a progenitor cell pool and the selection of progenitor cells for differentiation. As Notch signaling controls progenitor cell differentiation in many embryonic tissues, we investigated the involvement of this important developmental pathway in the embryonic pituitary. We report that expression of Notch signaling genes is spatially and temporally regulated in pituitary embryogenesis and implicate Notch2 in the differentiation of several cell lineages. Notch2, Notch3, and Dll1 are initially expressed by most cells within the pituitary primordium and become restricted to a subset of the progenitor cell pool as differentiated pituitary cells begin to appear. Mutations in the transcription factor Prop1 interfere with pituitary growth and cell specification, although the mechanism is unknown. Notch2 expression is nearly absent in the developing pituitaries of Prop1 mutant mice, but unaltered in some other panhypopituitary mutants, revealing that Prop1 is directly or indirectly required for normal Notch2 expression. Transgenic overexpression of Prop1 is not sufficient for enhancement of endogenous Notch2 expression, indicating that there are multiple inputs into this pathway. Dll3 is expressed only in the presumptive corticotrope and melanotrope cells. Analysis of Dll3 null mutants indicates that Dll3 is not required for specification of these two cell types, although there may be functional overlap with Dll1. The spatial and temporal expression patterns of Notch signaling genes in the pituitary suggest overlapping roles in pituitary growth and cell specification.
Incomplete differentiation of the anterior pituitary (AP) hormone-secreting cells can result in combined pituitary hormone deficiency (CPHD), in which patients display deficiencies in GH and at least one other AP hormone. The majority of familial CPHD cases are due to mutations in the pituitary transcription factor PROP1 (Prophet of Pit1). We have scanned for PROP1 mutations in a large consanguineous Indian CPHD pedigree and identified a novel 13-bp deletion in exon 2 that is predicted to generate a null allele. Assessment of GH, TSH, gonadotropin, and PRL levels in homozygous affected individuals indicated impaired production of these hormones by the AP. Interestingly, two of the affected subjects also displayed cortisol deficiency, which was progressive in one of these patients. This phenotypic feature is not normally associated with CPHD resulting from PROP1 mutation. These data show that PROP1 mutations can result in panhypopituitarism, the most severe form of AP deficiency, in which the production of all hormones is compromised and support a role for PROP1 in the maintenance and/or differentiation of all five hormone-secreting cell types. From a clinical perspective, these data indicate that the presence of an impaired pituitary-adrenal axis in CPHD patients does not exclude the possibility of an underlying PROP1 gene defect.
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