Ablation of the mouse Lhx3 gene also causes pituitary defects from a lack of pituitary cell differentiation. Lhx3 gene knockout mice are not viable, presumably due to nervous system deficits. Intriguingly, an LHX3 mutation that causes specific deletion of the C-terminus results in a variant form of the human disease involving pituitary CD 2314 hormone insufficiencies but not the deafness and neck stiffness that are correlated with LHX3 nervous system functions. Similarly, a Lhx3 W224ter mouse model is viable and recapitulates the dwarf phenotype resulting from pituitary hormone deficiencies but does not demonstrate defects linked to the nervous system. Further, whereas molecular studies have shown that LHX3 regulates nervous system genes within multiprotein complexes and that the N-terminal LIM domains and HD likely mediate these interactions, pituitary gene control requires the actions of additional LHX3 protein regions, including the critical C-terminal activation and repression domains. Together, these in vitro and in vivo observations are consistent with the hypothesis that the nervous system functions of LHX3 are molecularly separable in that the C-terminal part of the protein is only essential for full implementation of the pituitary roles of the protein. LHX3 proteins trans-activate pituitary hormone genes, such as alpha glycoprotein subunit, the TSH beta subunit, prolactin and other pituitary-expressed genes. LHX3 has been shown to interact with other CCMQ nuclear and regulatory proteins, such as NLI/LDB, ISL1/2, PIT1, RLIM, SLB, MRG1 and CREB Binding Protein. However, the role of the C-terminus in LHX3- mediated pituitary gene activation is not understood and the partners through which it exerts it functions have not been identified. In order to further understand the role of the LHX3 C-terminus in pituitary gene transcriptional regulation, we performed an affinity purification screen to identify proteins interacting with this important region of the protein. This approach identified interactions with components of the Inhibitor of histone acetyltransferase multi-subunit complex. INHAT is a multifunctional repressor that inhibits histone acetylation and modulates chromatin structure. The leucine-rich acidic nuclear protein, LANP and template activating factor 1b subunits of INHAT interact with the C-terminus of LHX3 and changes in LANP and TAF-1b levels modulate LHX3-mediated pituitary gene activation. LANP and TAF-1b are two main subunits of the INHAT multisubunit complex that acts as a multifunctional repressor to inhibit histone acetylation and modulate chromatin structure. In a mechanism known as ����histone masking����, INHAT binds to histone tails to prevent the substrate from interacting with histone acetyltransferases.