Endocrine Abstracts

LHX3 is a LIM homeodomain transcription factor necessary for proper development of the pituitary and central nervous system. Patients with mutations in coding regions of the LHX3 gene have complex syndromes including combined pituitary hormone deficiency and nervous system defects resulting in symptoms such as dwarfism, thyroid insufficiency, infertility, and developmental delay. Although previous studies from our group and others have identified promoter and intronic elements of LHX3 that are important for basal gene expression in vitro, the mechanisms by which the LHX3 gene is regulated in vivo were not known. Using transgenic mouse models and bioinformatic approaches, we have mapped conserved enhancer and repressor regions that direct tissue-specific expression to the pituitary gland and spinal cord in a pattern consistent with endogenous expression. Several transferable cis elements can individually guide nervous system expression; however, a 180 bp minimal enhancer is alone sufficient to confer specific expression in the developing pituitary. Within this sequence, tandem binding sites recognized by the ISL1 LIM homedomain protein are essential for enhancer activity in the pituitary and spine and a PITX1 bicoid class homeodomain element is required for spatial patterning in the developing pituitary. This study establishes ISL1 as a novel transcriptional regulator of LHX3 and describes a mechanism for regulation by PITX1. Ongoing research focuses on lineage tracing experiments using an enhancer-directed Cre recombinase mouse model. This approach will identify what differentiated cells and their progeny originated from cells with enhancer-directed expression. Characterization of novel genetic defects will facilitate patient treatment and enable genetic counseling. Sources of Research Support: NIH HD42024 to SJR.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.