Our experiments demonstrate that LHX3 interacts with the acidic carboxyl domains of the TAF-1b and LANP INHAT components. It has been described that LANP and TAF-1b similarly interact with each other through their carboxyl terminal acidic domains. INHAT components have been described as both facilitating transcriptional repression and activation via cofactor associations. INHAT proteins participate in histone masking, as well as binding of target gene promoter sequences for gene repression. Our data also indicate LHX3, LANP, and TAF-1b associate with the LHX3-responsive aGSU/ Cga promoter in mouse gonadotrope cells; and INHAT protein overexpression inhibits LHX3-driven pituitary gene activation. It is possible that LHX3 expression during pituitary development results in LHX3-INHAT interactions that function to prevent gene repression by INHAT. LHX3 may therefore work both indirectly by disrupting core INHAT proteins in a ‘‘de-repression’’ function, and directly by serving as a DNA-binding transcription factor on pituitary target genes. In this model, INHAT association with promoter DNA, through histone-binding and potentially other unknown co-factor, facilitates gene silencing. Upon LHX3 expression, and possible association with the CBP global coactivator, interaction with the acidic domains of TAF-1b and LANP by the LHX3 C-terminus may disrupt the INHAT complex and thus cause its dissociation from promoter chromatin. This INHAT dissociation would then allow for subsequent transactivation of the target by LHX3 and CBP. The experiments described here have identified INHAT components that are broadly expressed. In this context, LHX3 therefore could act as a specificity factor in the expression of pituitary tissue-specific genes with its functions determined by the chromatin microenvironment. However, we also hypothesize that the LHX3 C-terminus and other parts of the protein may interact with co-factor proteins that contribute to cell-specific functions of LHX3 during development. Another possible mechanism may involve direct regulation of LHX3 by INHAT factors. Other proteins associated with chromatin remodeling and regulation have been shown to directly regulate transcription factors. In the heart, HOPX and HDAC2 interact to modulate GATA4 acetylation. It is not known if LHX3 is PF-2341066 acetylated, but it is also possible that the INHAT complex may mask LHX3 acetylation and therefore block activation of pituitary genes. Further experiments need to be performed in order to test these models. We have described novel protein partners of the LHX3 regulatory protein that is critical for the development of both nervous and endocrine system tissues. Because mutations affecting the regions of the LHX3 protein involved in these interactions are associated with severe pediatric human diseases, these observations may have relevance to our understanding of the aberrant mechanisms underlying such diseases and may provide insights into the etiology of human endocrine diseases and allow future therapies and genetic counseling. Huntington disease is a devastating, incurable neurodegenerative condition, caused by CAG repeat expansion in the IT15 gene, which encodes an expanded polyglutamine tract in the target protein, huntingtin. One barrier to rapid development of therapies is the difficulty and expense in carrying out preclinical in vivo trials of candidate therapeutic compounds. This is due to multiple factors, especially inter-animal variability that requires large numbers of animals over relatively long study periods, and the challenge of drug delivery to the CNS. The R6/2 mouse is widely used to study HD pathogenesis and test therapeutic leads. It expresses the first exon of the expanded Htt gene, which produces a highly neurotoxic and aggregation-prone protein. It exhibits rapid and uniform symptom onset at about 5-6 weeks of age, with death at about 14-19 weeks. The R6/2 mouse has been reported previously to develop retinopathy, but the histopathological descriptions have been only of the later-stage retinal phenotype at about 10 weeks of age, and no functional studies have been reported in this line. By contrast, the R6/1 line, which also expresses Htt exon 1, has later onset, and much later death. Its retinal pathology has been more thoroughly studied. The retinal phenotype appears to be virtually identical in character in the two lines, differing only in time of onset and rate of degeneration.