Mechanisms underlying pituitary hypoplasia and failed cell specification in Lhx3-deficient mice.
The LIM homeodomain transcription factor, LHX3, is essential for pituitary development in mouse and man. Lhx3 engineered null mice have profound pituitary hypoplasia that we find is attributable to an increase in cell death early in pituitary development. Dying cells are localized to regions of TPIT expression indicating that cell death may contribute to the severe reduction in differentiated corticotrope cells and lower expression of the corticotrope transcription factors, TPIT and NEUROD1. Lhx3 deficiency also results in dorsal ectopic expression of transcription factors characteristic of gonadotropes, SF1 and ISL1, but no gonadotropin expression. This apparent disturbance of cell differentiation may be due, in part, to loss of NOTCH2. NOTCH2 is normally expressed in the pituitary at the boundary between dorsal, proliferating cells and ventral, differentiating cells and is important for maintaining dorsal-ventral patterning in other organs. Thus, Lhx3 contributes significantly to pituitary development by maintaining normal dorsal-ventral patterning, cell survival, and normal expression of corticotrope-specific transcription factors, which are necessary for repressing ectopic gonadotrope differentiation.
Department of Human Genetics, The University of Michigan, Medical School, 4909 Buhl Bldg., Ann Arbor, MI 48109-0618, USA.
Buffy S
BS
Ellsworth
Darcy L
DL
Butts
Sally A
SA
Camper
D000818:Animals; D017209:Apoptosis; D004622:Embryo, Mammalian; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D060850:LIM-Homeodomain Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D010902:Pituitary Gland / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D051883:Receptor, Notch2 / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism; D014157:Transcription Factors
D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; C094898:Lhx3 protein; C497765:Notch2 protein, mouse; D051883:Receptor, Notch2; D020825:T-Box Domain Proteins; C424031:Tbx19 protein, mouse; D014157:Transcription Factors