International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 145 - BIOINFORMATICS AND GENE DISCOVERY APPROACH TO PITUITARY DEVELOPMENT: Prop1 AND NOTCH SIGNALING

Raetzman L T
Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109-0638, USA

Co-Authors: 1) Brinkmeier ML, 3) Ross S A, 4) Carninci P, 4) Shiraki T, 4) Arakawa T, 4)Kawai J, 2)Lyons RH, 1) Ward R D, 3) Cook S, 5) Dunwoodie S L, 1) Camper SA, 3) Thomas P Q, 4) Hayashizaki Y.
Institutions: 1) Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109-0638, USA, 2) Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109-0638, USA. 3) Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia. 4) Laboratory for Genome Exploration Research Group, RIKEN Genomic Sciences Center (GSC), RIKEN Yokohama Institute, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. 5) Victor Chang Cardiac Research Institute, St Vincent's Hospital, Darlinghurst, NSW 2010, Australia

Pituitary gland development requires the specification and proliferation of 5 different hormone producing cell types. Mutations in the homeodomain transcription factor Prop1 cause combined pituitary hormone deficiency in humans and mice. Prop1 deficiency appears to prevent progenitors from leaving the proliferative zone and migrating ventrally to populate the anterior lobe where differentiated cells reside. We employed a gene discovery approach to identify Prop1 target genes and discover its mechanism of action. We prepared three full length cDNA libraries from pituitary primordia of normal (at e12.5 and e14.5) and Prop1 mutant (e14.5) embryos using the cap trapper method, sequenced over 30,000 clones, and established a searchable database using GO terminology. Several Notch signaling genes are present in the libraries. Notch2, Notch3 and Dll1 are initially expressed by most cells within the pituitary primordium and become restricted to a subset of progenitors as differentiated pituitary cells begin to appear. Notch2 expression is nearly absent in the developing pituitaries of Prop1 mutant mice, but unaltered in some other panhypopituitary mutants, revealing that Prop1 is specifically required for normal Notch signalling. In addition to Notch, a known regulator of cell proliferation and differentiation, many cell cycle control and cell adhesion genes are in the developing pituitary libraries. Of over 200 Riken cDNA libraries, the highest frequency of novel clones was found in the e14.5 pituitary library (24%), indicating the utility of cDNA libraries prepared from small tissues for gene discovery. These libraries are a rich resource for understanding how Prop1 promotes pituitary differentiation.


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