Functional relationship between LHX4 and POU1F1 in light of the LHX4 mutation identified in patients with pituitary defects.

CONTEXT: Pituitary development depends on the actions of a large number of transcription factors. Among them, LHX4 is believed to play a crucial role, as suggested by the dominantly inherited GH deficiency associated with the recently identified LHX4 mutation, although the precise mechanism underlying this phenotype is still to be elucidated.
OBJECTIVE: The objective of this study was to gain insight into both the function of LHX4 and the pathophysiology of the LHX4-related syndrome. We sought potential targets of this factor and assessed the abilities of various recombinant LHX4 isoforms expressed in Chinese hamster ovary cells to bind to and activate the POUI1F1 upstream regulatory sequence.
RESULTS: We show that normal LHX4 binds to a human-specific element and subsequently activates transcription from the proximal upstream regulatory sequence of POUIF1, a gene encoding a POU homeodomain transcription factor known as the main regulator of GH expression. As shown in this cell system, the mutant LHX4 proteins predicted by the defect identified in patients fail to bind to and subsequently activate the POU1F1 regulatory sequence, but do not impair the ability of normal LHX4 to activate this target.
CONCLUSIONS: Such findings are consistent with the existence, in humans, of an LHX4-driven pathway leading to the expression of GH through transcriptional activation of POU1F1. They argue against a dominant-negative effect of the mutant LHX4 proteins over normal LHX4. Finally, they provide a clear-cut evaluation of the functional consequences, at the molecular level, of the LHX4 mutation, which, through disruption of the former pathway, would account for one key feature of the LHX4-related syndrome.