{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n LHX4 is a LIM‐homeodomain transcription factor that plays a pivotal role in early neuro‐endocrine development by regulating the differentiation, survival, and function of pituitary cells as well as other neuronal populations. Experimental studies in mouse models and human patients have demonstrated that LHX4 is indispensable for normal pituitary formation, where it activates key target genes such as POU1F1 and α‐glycoprotein subunit (αGSU) to promote the later specification and expansion of hormone‐producing cells. Its function appears to be mediated through its capacity to bind DNA and interact with other transcriptional regulators to control the expression of genes essential for growth, reproduction, and metabolic homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its established role in pituitary hormone gene activation, LHX4 functions in overlapping transcriptional networks with other LIM‐homeodomain proteins such as LHX3. In gonadotrope cells, for example, LHX4 is capable of inducing transcription from the FSHβ promoter, thereby contributing to reproductive function and underscoring potential functional redundancy and cooperation among these factors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Clinical studies have further revealed that heterozygous mutations or deletions in LHX4 lead to variable, often progressive, combined pituitary hormone deficiencies that may be associated with pituitary hypoplasia, ectopic posterior pituitary, and even extrapituitary malformations affecting brain and craniofacial structures. Severe or recessive alterations in LHX4 have been linked not only to growth hormone deficiency but also to defects in anterior pituitary cell survival and hormone production, which together manifest as congenital hypopituitarism with diverse phenotypes, including lethal outcomes in some cases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, emerging pharmacogenomic evidence has associated specific genetic markers within LHX4 with variations in growth responses to recombinant human growth hormone therapy, further highlighting its role in endocrine regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, LHX4 functions as a master regulator within a complex transcriptional network that is essential for orchestrating pituitary development and maintaining proper endocrine function. Its activity in promoting the expression of critical hormone regulatory genes and its interaction with other developmental transcription factors underscore its pleiotropic roles in both the formation of the pituitary gland and broader aspects of brain morphogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "K Machinis, J Pantel, I Netchine, et al. 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