# LHX1

## Overview
LHX1 is a gene located on human chromosome 17q12 that encodes the LIM homeobox 1 protein, a transcription factor involved in various developmental processes. The LHX1 protein is characterized by its LIM domains, which facilitate protein-protein interactions, and a homeodomain that binds DNA, crucial for its role in gene regulation (Bozzi1996The). Functionally, LHX1 is essential in early embryonic development, influencing cell fate determination and morphogenesis through its regulation of gene transcription (Costello2015Lhx1). It is particularly significant in the development of the definitive endoderm and other critical structures during embryogenesis (Costello2015Lhx1). Mutations in the LHX1 gene are associated with developmental disorders such as Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, highlighting its clinical importance (Singh2021LIM).

## Structure
The molecular structure of the LHX1 protein, encoded by the human LHX1 gene, is characterized by several distinct domains essential for its function as a transcription factor. The protein includes two cysteine-rich LIM domains located at the N-terminus, which are crucial for mediating protein-protein interactions. These LIM domains are entirely contained within the first and second exons of the gene (Bozzi1996The). The central part of LHX1 features a DNA-binding homeodomain (HD), which is split between the third and fourth exons, playing a pivotal role in regulating gene expression (Bozzi1996The).

At the C-terminus, LHX1 possesses a transactivation domain (CTD), involved in the activation of downstream genes (Denio2016Research). Additionally, the protein's ability to form dimers, a significant aspect of its quaternary structure, was demonstrated using a split-ubiquitin yeast two-hybrid system, indicating complex interaction capabilities (Denio2016Research).

While the primary, secondary, and tertiary structures of LHX1 are not explicitly detailed in the available literature, the described domains and their functional implications provide insight into the protein's overall structural organization and its role in cellular processes.

## Function
LHX1, a LIM homeobox transcription factor, plays a pivotal role in early embryonic development processes by regulating gene transcription crucial for cell fate determination and morphogenesis. It is activated by the T-box transcription factor Eomes, influenced by Nodal/Smad signaling pathways, and is essential for the development of the definitive endoderm lineage, anterior mesendoderm, and midline progenitors (Costello2015Lhx1). LHX1 functions by binding primarily to enhancer regions, rather than promoter regions, modulating the expression of key developmental genes such as Otx2 and Foxa2. This binding activity is critical for the correct patterning of the anterior neuroectoderm and the establishment of the left-right body axis (Costello2015Lhx1).

In the cellular context, LHX1 interacts with other transcription factors like Otx2, Foxa2, and Ldb1, forming complexes that regulate crucial developmental processes. These interactions are vital for the transcriptional regulation of several key genes, including those in the Wnt pathway, which are essential for the development of axial mesoderm-derived structures and the anterior mesendoderm, node, and midline structures (Costello2015Lhx1). Additionally, LHX1's role extends to influencing cellular architecture by regulating the expression of genes important for cytoskeletal organization and extracellular matrix composition, such as Shroom3 and Col2a1 (Costello2015Lhx1).

## Clinical Significance
LHX1 mutations and alterations are closely associated with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, a condition characterized by the congenital absence of the uterus and part of the vagina, despite normal ovarian function. This syndrome results from disruptions in the normal development of the müllerian ducts, which LHX1 is crucial for developing. Specific deletions in the region of chromosome 17q12 that includes LHX1 have been observed in patients with MRKH syndrome (Singh2021LIM; Ledig2012Frame). Additionally, various mutations such as frameshift and missense mutations in LHX1 have been identified in MRKH patients, affecting the gene's function and its ability to regulate the expression of target genes crucial for normal reproductive development (Singh2021LIM; Zhang2017Identification).

Moreover, LHX1 is essential for the development of both the müllerian ducts and Wolffian ducts, the latter forming parts of the male reproductive system. Mutations in LHX1 thus disrupt normal reproductive tract development, leading to the symptoms observed in MRKH syndrome (Ledig2012Frame). In animal models, targeted inactivation of Lhx1 results in a phenotype that includes aplasia of the Müllerian ducts, further underscoring the gene's critical role in reproductive system development (Ledig2012Frame).

## Interactions
LHX1 interacts with a variety of proteins and nucleic acids, playing a crucial role in transcriptional regulation and developmental processes. It forms a tripartite transcription factor complex with OTX2 and FOXA2, which is significant in mesendodermal cells, and is involved in anterior patterning defects and node morphogenesis (Costello2015Lhx1). Additionally, LHX1 interacts with LDB1, enhancing its DNA-binding ability, which is essential for its function in embryonic development (McMahon2019Mechanistic). This interaction with LDB1 is also crucial in forming complexes that regulate gene expression in the pancreas, particularly in β-cell lines and islets (Bethea2019The).

LHX1 also binds directly to nucleic acids, with ChIP-seq experiments showing its binding at enhancer elements and regulatory regions of genes critical for embryonic development, such as Hesx1, Embigin, and Fzd8 (Costello2015Lhx1). In the context of kidney development, LHX1 forms a complex with LDB1 and interacts with the Fryl protein, playing a role in regulating microRNA expression crucial for kidney specification (Espiritu2018The).

These interactions highlight LHX1's role in coordinating transcriptional regulation necessary for proper embryonic development across various organ systems.


## References


[1. (Denio2016Research) Elon K. Denio, Paul M. Kelly, and Cuong Q. Diep. Research article: protein-protein interaction analysis reveals a novel function of thelhx1transcription factor in zebrafish. BIOS, 87(2):31–38, May 2016. URL: http://dx.doi.org/10.1893/bios-d-14-00038.1, doi:10.1893/bios-d-14-00038.1. (5 citations) 10.1893/bios-d-14-00038.1](https://doi.org/10.1893/bios-d-14-00038.1)

[2. (Zhang2017Identification) Wei Zhang, Xueya Zhou, Liyang Liu, Ying Zhu, Chunmei Liu, Hong Pan, Qiong Xing, Jing Wang, Xi Wang, Xuegong Zhang, Yunxia Cao, and Binbin Wang. Identification and functional analysis of a novel lhx1 mutation associated with congenital absence of the uterus and vagina. Oncotarget, 8(5):8785–8790, January 2017. URL: http://dx.doi.org/10.18632/oncotarget.14455, doi:10.18632/oncotarget.14455. (15 citations) 10.18632/oncotarget.14455](https://doi.org/10.18632/oncotarget.14455)

[3. (McMahon2019Mechanistic) Riley McMahon, Tennille Sibbritt, Nazmus Salehin, Pierre Osteil, and Patrick P. L. Tam. Mechanistic insights from the lhx1‐driven molecular network in building the embryonic head. Development, Growth & Differentiation, 61(5):327–336, May 2019. URL: http://dx.doi.org/10.1111/dgd.12609, doi:10.1111/dgd.12609. (13 citations) 10.1111/dgd.12609](https://doi.org/10.1111/dgd.12609)

[4. (Espiritu2018The) Eugenel B. Espiritu, Amanda E. Crunk, Abha Bais, Daniel Hochbaum, Ailen S. Cervino, Yu Leng Phua, Michael B. Butterworth, Toshiyasu Goto, Jacqueline Ho, Neil A. Hukriede, and M. Cecilia Cirio. The lhx1-ldb1 complex interacts with furry to regulate microrna expression during pronephric kidney development. Scientific Reports, October 2018. URL: http://dx.doi.org/10.1038/s41598-018-34038-x, doi:10.1038/s41598-018-34038-x. (11 citations) 10.1038/s41598-018-34038-x](https://doi.org/10.1038/s41598-018-34038-x)

[5. (Ledig2012Frame) S. Ledig, S. Brucker, G. Barresi, J. Schomburg, K. Rall, and P. Wieacker. Frame shift mutation of lhx1 is associated with mayer-rokitansky-kuster-hauser (mrkh) syndrome. Human Reproduction, 27(9):2872–2875, June 2012. URL: http://dx.doi.org/10.1093/humrep/des206, doi:10.1093/humrep/des206. (99 citations) 10.1093/humrep/des206](https://doi.org/10.1093/humrep/des206)

[6. (Singh2021LIM) Neha Singh, Domdatt Singh, and Deepak Modi. Lim homeodomain (lim-hd) genes and their co-regulators in developing reproductive system and disorders of sex development. Sexual Development, 16(2–3):147–161, September 2021. URL: http://dx.doi.org/10.1159/000518323, doi:10.1159/000518323. (8 citations) 10.1159/000518323](https://doi.org/10.1159/000518323)

[7. (Bozzi1996The) Fabio Bozzi, Stefano Bertuzzi, Dario Strina, Cettina Giannetto, Paolo Vezzoni, and Anna Villa. The exon–intron structure of humanlhx1 gene. Biochemical and Biophysical Research Communications, 229(2):494–497, December 1996. URL: http://dx.doi.org/10.1006/bbrc.1996.1832, doi:10.1006/bbrc.1996.1832. (16 citations) 10.1006/bbrc.1996.1832](https://doi.org/10.1006/bbrc.1996.1832)

[8. (Costello2015Lhx1) Ita Costello, Sonja Nowotschin, Xin Sun, Arne W. Mould, Anna-Katerina Hadjantonakis, Elizabeth K. Bikoff, and Elizabeth J. Robertson. Lhx1 functions together with otx2, foxa2, and ldb1 to govern anterior mesendoderm, node, and midline development. Genes & Development, 29(20):2108–2122, October 2015. URL: http://dx.doi.org/10.1101/gad.268979.115, doi:10.1101/gad.268979.115. (101 citations) 10.1101/gad.268979.115](https://doi.org/10.1101/gad.268979.115)

[9. (Bethea2019The) Maigen Bethea, Yanping Liu, Alexa K. Wade, Rachel Mullen, Rajesh Gupta, Vasily Gelfanov, Richard DiMarchi, Sushant Bhatnagar, Richard Behringer, Kirk M. Habegger, and Chad S. Hunter. The islet-expressed lhx1 transcription factor interacts with islet-1 and contributes to glucose homeostasis. American Journal of Physiology-Endocrinology and Metabolism, 316(3):E397–E409, March 2019. URL: http://dx.doi.org/10.1152/ajpendo.00235.2018, doi:10.1152/ajpendo.00235.2018. (15 citations) 10.1152/ajpendo.00235.2018](https://doi.org/10.1152/ajpendo.00235.2018)