The long term goal of this research program is to understand the mechanisms that underlie human pituitary development and function and to apply that knowledge to the prevention and treatment of pituitary diseases. The anterior pituitary gland secretes polypeptide hormones that are critical for many aspects of human development and physiology, including growth, reproduction, the stress response, metabolic homeostasis, and lactation. Diseases involving pituitary dysfunction therefore can involve severe syndromes affecting many tissues and systems. During embryogenesis, the actions of transcription factors, such as the LHX3 homeodomain protein, govern the establishment of the hormone-secreting pituitary cell types. This laboratory and others have recently described that mutations in the LHX3 gene cause combined pituitary hormone deficiency diseases, and other symptoms such as nervous system problems, in children. The biochemical mechanism by which proteins such as LHX3 exert their critical functions is poorly understood. We have, however, recently determined that mutations affecting distinct parts of the LHX3 protein are correlated with specific disease outcomes: mutations only compromising the carboxyl terminus are associated with a more restricted disease involving pituitary hormone deficiency but not nervous system problems. This proposal tests hypotheses involving the mechanism of LHX3-associated hormone deficiency diseases. The mechanism of LHX3-mediated transcription will be investigated by characterizing a protein complex that interacts with the carboxyl terminal domains of LHX3 that are required for pituitary gene regulation. To further understand the novel form of LHX3-associated disease involving loss of the protein carboxyl terminus, gene targeting techniques will be used to generate a mouse model of the disease carrying an equivalent mutation, allowing molecular and cellular characterization of the disease symptoms and progression, an approach that is not possible in the patients. In addition, the mechanisms that regulate transcription of the human LHX3 gene will be determined using transgenic animal approaches. Regulatory regions identified in these studies will provide candidate sequences for tests of involvement in pituitary diseases of unknown etiology. The proposed experiments will allow the laboratory to continue to translate basic laboratory findings to the clinic through established collaborations with physicians, permitting new diagnostic tests, allowing genetic counseling of affected families, and facilitating improved treatment of the patients. Further, clinical collaborations will continue to provide information that enhances our understanding of the basic mechanisms of pituitary development, thereby allowing the formulation of new research hypotheses.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD042024-10
Application #
8197596
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Javois, Lorette Claire
Project Start
2002-04-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
10
Fiscal Year
2012
Total Cost
$268,160
Indirect Cost
$86,396
Name
Indiana University-Purdue University at Indianapolis
Department
Physiology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Malik, Raleigh E; Rhodes, Simon J (2014) The role of DNA methylation in regulation of the murine Lhx3 gene. Gene 534:272-81
Hunter, Chad S; Malik, Raleigh E; Witzmann, Frank A et al. (2013) LHX3 interacts with inhibitor of histone acetyltransferase complex subunits LANP and TAF-1* to modulate pituitary gene regulation. PLoS One 8:e68898
Prince, Kelly L; Colvin, Stephanie C; Park, Soyoung et al. (2013) Developmental analysis and influence of genetic background on the Lhx3 W227ter mouse model of combined pituitary hormone deficiency disease. Endocrinology 154:738-48
Bechtold-Dalla Pozza, Susanne; Hiedl, Stefan; Roeb, Julia et al. (2012) A recessive mutation resulting in a disabling amino acid substitution (T194R) in the LHX3 homeodomain causes combined pituitary hormone deficiency. Horm Res Paediatr 77:41-51
Yusuf, Dimas; Butland, Stefanie L; Swanson, Magdalena I et al. (2012) The transcription factor encyclopedia. Genome Biol 13:R24
Mullen, Rachel D; Park, Soyoung; Rhodes, Simon J (2012) A distal modular enhancer complex acts to control pituitary- and nervous system-specific expression of the LHX3 regulatory gene. Mol Endocrinol 26:308-19
Colvin, Stephanie C; Malik, Raleigh E; Showalter, Aaron D et al. (2011) Model of pediatric pituitary hormone deficiency separates the endocrine and neural functions of the LHX3 transcription factor in vivo. Proc Natl Acad Sci U S A 108:173-8
Prince, Kelly L; Walvoord, Emily C; Rhodes, Simon J (2011) The role of homeodomain transcription factors in heritable pituitary disease. Nat Rev Endocrinol 7:727-37
Kelberman, D; Turton, J P G; Woods, K S et al. (2009) Molecular analysis of novel PROP1 mutations associated with combined pituitary hormone deficiency (CPHD). Clin Endocrinol (Oxf) 70:96-103
Colvin, Stephanie C; Mullen, Rachel D; Pfaeffle, Roland W et al. (2009) LHX3 and LHX4 transcription factors in pituitary development and disease. Pediatr Endocrinol Rev 6 Suppl 2:283-90

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