International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

I10. Homeobox Genes in Pituitary Development and Cell Specification

S.A.Camper123, H.Suh3, P.Eswara1, P.J.Gage1
1Departments of Human Genetics and 2Internal Medicine, 3Graduate Program in Neuroscience, University of Michigan, Ann Arbor, MI 48109.

Several genes encoding homeobox transcription factors are important for normal pituitary development and hormone production (1, 2). Lhx3, Hesx1, Prop1, and Pit1 act sequentially in a genetic hierarchy to stimulate expansion of the pituitary primordium an initiate cell commitment (3). The phenotypes of mice with mutations in these genes correlate with the features of human patients with lesions in homologous genes. Loss of LHX3, POU1F1 (PIT1), or PROP1 function results in combined pituitary hormone deficiency (CPHD), and disruption of HESX1 causes both CPHD and septo-optic dysplasia (4). Since all cases of CPHD cannot be explained by mutations in these genes, we used motif screens to identify novel cDNAs expressed in the pituitary primordium and cloned Pitx2 (5). Lesions in PITX2 are one cause of Rieger syndrome, a disorder characterized by eye, tooth and umbilical defects, with occasional heart defects and pituitary growth hormone (GH) insufficiency (6). Mice heterozygous for a hypomorphic (Pitx2neo) or null (Pitx2null) allele have a low frequency of abnormalities consistent with RGS. Analysis of homozyotes for these alleles revealed a dosage sensitive requirement of multiple organs for Pitx2 (7). The neo homozygotes survive until birth but the null homozygotes die earlier with more severe disruptions in heart, eye, body wall, brain and pituitary development. The pituitary primordium of Pitx2null/null embryos does not undergo expansion, and although expression of Lhx3 is detectable, Hesx1 transcripts are absent. These results suggest that Pitx2 acts very early in the hierarchy of genes regulating pituitary organogenesis. The pituitary morphology in Pitx2neo/neo mice is normal, but the reduction in Pitx2 dosage lowers transcription of several hormone genes: luteinizing hormone, follicle stimulating hormone, thyroid stimulating hormone, and GH. Reduced Pitx2 transcripts cause the loss of two transcription factors critical for gonadotrope specification and function, Gata2 and Egr1. This suggests Pitx2 is required early in the genetic hierarchy for initial expansion of the pituitary primordium and for later cell specification and hormone production. Loss of function mutations in the related Pitx1 gene cause milder reductions in hormone gene transcription (8, 9). Double mutant analysis reveals that Pitx1 and Pitx2 have important overlapping functions in development of the pituitary primordia. Preliminary data suggest that Pitx2 interacts with other early-acting homeobox genes such as Lhx3 and Lhx4, which are also necessary for early expansion of the pituitary primordium (10). The extensive genetic overlap suggests that some cases of CPHD may be caused by digenic or complex inheritance of these pituitary transcription factor genes.

(NIH grants HD34283 and HD30248, Glaucoma Research Foundation)

1. Burrows, Douglas, Seasholtz, Camper, Trends in Endo & Metab. 10, 343 (1999).

2. Watkins-Chow, Camper, Trends in Genetics 14, 284 (1998).

3. Gage, et al., Molecular Endocrinology 10, 1570 (1996).

4. Dattani, et al., Nature Genetics 19, 125 (1998).

5. Gage, Camper, Human Molecular Genetics 6, 457 (1997).

6. Semina, et al., Nature Genetics 14, 392 (1996).

7. Gage, Suh, Camper, Development 126, 4643 (1999).

8. Szeto, et al., Genes & Development 13, 484 (1999).

9. Lanctot,et al., Development 126, 1805 (1999).

10. H. Sheng, et al., Science 278, 1809 (1997).

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