Endocrine Abstracts (2011) 26 P207

Mechanism of anterior pituitary gene regulation by LHX3 in paediatric combined pituitary hormone deficiency

R Malik, C Hunter, S Colvin & S Rhodes

Indiana School of Medicine, Indianapolis, Indiana, USA.

LHX3, a member of the LIM-homeodomain family of developmental transcription factors, is required for establishment of mammalian anterior pituitary hormone-secreting cell types as well as the formation of specialized neurons of the nervous system. Paediatric patients with pituitary insufficiency are sometimes diagnosed with combined pituitary hormone deficiency disease (CPHD). This disease can be linked to mutations in essential pituitary developmental transcription factor genes, including LHX3.

Various mutations in LHX3 have been found to cause CPHD and we recently created a mouse gene knock-in model of CPHD patients whose LHX3 gene encodes a truncated protein, resulting from an early termination signal at residue 224 (W224Ter). This mutation differs from other LHX3 mutations in that the patients (and mouse model) do not present with nervous system defects but have pituitary insufficiency. Therefore, we hypothesized that the carboxyl-terminus (C-terminus) of LHX3 is necessary for pituitary development but not nervous system development. We have previously reported that the C-terminus of LHX3 contains activation and repression domains required for pituitary gene activation. In order to understand the mechanism of LHX3-mediated pituitary gene regulation, we have characterized co-regulatory proteins that interact with the C-terminus of LHX3. An affinity purification screen of pituitary proteins identified members of the inhibitor of histone acetyltransferase (INHAT) transcriptional repression complex as interacting with the LHX3 C-terminus. Protein–protein interaction assays indicated that LHX3 binds to specific members of the INHAT complex. Deletion analyses demonstrated that the C-terminus of each INHAT subunit was essential to bind to LHX3. Chromatin immunoprecipitation (ChIP) assays indicate that INHAT components are present with LHX3 at the gene loci of predicted LHX3 pituitary gene targets. The INHAT complex also repressed LHX3-dependent pituitary gene expression in functional assays. This study provides further insight into the mechanism governing anterior pituitary gene regulation by regulatory transcription factor proteins.

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