Genomes and Genes
Gene Symbol: Lhx3
Description: LIM homeobox protein 3
Alias: Lim3, P-LIM, mLIM3, mLim-3, LIM/homeobox protein Lhx3, LIM homeo box protein 3, homeobox protein LIM-3, homeobox protein P-LIM
- Gadd M, Bhati M, Jeffries C, Langley D, Trewhella J, Guss J, et al. Structural basis for partial redundancy in a class of transcription factors, the LIM homeodomain proteins, in neural cell type specification. J Biol Chem. 2011;286:42971-80 pubmed publisher..Two paralogous pairs of LIM homeodomain proteins, LIM homeobox protein 3/4 (Lhx3/Lhx4) and Islet-1/2 (Isl1/Isl2), are expressed in developing ventral motor neurons...
- Bach I, Rodriguez Esteban C, Carriere C, Bhushan A, Krones A, Rose D, et al. RLIM inhibits functional activity of LIM homeodomain transcription factors via recruitment of the histone deacetylase complex. Nat Genet. 1999;22:394-9 pubmed..We conclude that Rlim is a novel corepressor that recruits histone deacetylase-containing complexes to the LIM domain. ..
- McGillivray S, Bailey J, Ramezani R, Kirkwood B, Mellon P. Mouse GnRH receptor gene expression is mediated by the LHX3 homeodomain protein. Endocrinology. 2005;146:2180-5 pubmed..b>LHX3, a member of the LIM homeodomain family, binds the -298 ATTA site in vitro as well as to the endogenous GnRHR ..
- Shirasaki R, Lewcock J, Lettieri K, Pfaff S. FGF as a target-derived chemoattractant for developing motor axons genetically programmed by the LIM code. Neuron. 2006;50:841-53 pubmed..the identity of limb-innervating motor neurons to that of dermomyotome-innervating MMCm cells using the LIM factor Lhx3 induces FGFR1 expression and shifts an increased number of motor axons to an FGF-responsive state...
- Thaler J, Lee S, Jurata L, Gill G, Pfaff S. LIM factor Lhx3 contributes to the specification of motor neuron and interneuron identity through cell-type-specific protein-protein interactions. Cell. 2002;110:237-49 pubmed..b>Lhx3 is involved in the generation of two adjacent, but distinct, cell types for locomotion, motor neurons and V2 ..
- Arber S, Han B, Mendelsohn M, Smith M, Jessell T, Sockanathan S. Requirement for the homeobox gene Hb9 in the consolidation of motor neuron identity. Neuron. 1999;23:659-74 pubmed..These findings show that HB9 has an essential function in consolidating the identity of postmitotic MNs. ..
- Sharma K, Sheng H, Lettieri K, Li H, Karavanov A, Potter S, et al. LIM homeodomain factors Lhx3 and Lhx4 assign subtype identities for motor neurons. Cell. 1998;95:817-28 pubmed..We show that LIM homeodomain factors Lhx3 and Lhx4 are expressed transiently in motor neurons whose axons emerge ventrally from the neural tube (v-MN)...
- Colvin S, Malik R, Showalter A, Sloop K, Rhodes S. Model of pediatric pituitary hormone deficiency separates the endocrine and neural functions of the LHX3 transcription factor in vivo. Proc Natl Acad Sci U S A. 2011;108:173-8 pubmed publisher..To better understand these diseases, we have created a unique mouse model of CPHD with a targeted knockin mutation (Lhx3 W227ter), which is a model for the human LHX3 W224ter disease...
- Thaler J, Harrison K, Sharma K, Lettieri K, Kehrl J, Pfaff S. Active suppression of interneuron programs within developing motor neurons revealed by analysis of homeodomain factor HB9. Neuron. 1999;23:675-87 pubmed..Thus, MNs actively suppress interneuron genetic programs to establish their identity...
- Cushman L, Camper S. Molecular basis of pituitary dysfunction in mouse and human. Mamm Genome. 2001;12:485-94 pubmed
- Sloop K, Dwyer C, Rhodes S. An isoform-specific inhibitory domain regulates the LHX3 LIM homeodomain factor holoprotein and the production of a functional alternate translation form. J Biol Chem. 2001;276:36311-9 pubmed publisherThe LHX3 LIM homeodomain transcription factor is required for pituitary development and motor neuron specification. The Lhx3 gene encodes two isoforms, LHX3a and LHX3b, that differ in their amino-terminal sequences...
- Bach I, Rhodes S, Pearse R, Heinzel T, Gloss B, Scully K, et al. P-Lim, a LIM homeodomain factor, is expressed during pituitary organ and cell commitment and synergizes with Pit-1. Proc Natl Acad Sci U S A. 1995;92:2720-4 pubmed..The LIM domain of P-Lim specifically interacts with the Pit-1 POU domain and is required for synergistic interactions with Pit-1, but not for basal transcriptional activation events. ..
- Sheng H, Zhadanov A, Mosinger B, Fujii T, Bertuzzi S, Grinberg A, et al. Specification of pituitary cell lineages by the LIM homeobox gene Lhx3. Science. 1996;272:1004-7 pubmed..Targeted gene disruption in mice showed that Lhx3, a LIM homeobox gene expressed in the pituitary throughout development, is essential for differentiation and ..
- Takuma N, Sheng H, Furuta Y, Ward J, Sharma K, Hogan B, et al. Formation of Rathke's pouch requires dual induction from the diencephalon. Development. 1998;125:4835-40 pubmed..Second, FGF8 is necessary for activation of the key regulatory gene Lhx3 and subsequent development of the pouch rudiment into a definitive pouch...
- Ostendorff H, Peirano R, Peters M, Schlüter A, Bossenz M, Scheffner M, et al. Ubiquitination-dependent cofactor exchange on LIM homeodomain transcription factors. Nature. 2002;416:99-103 pubmed..Our data provide a mechanistic basis for cofactor exchange on DNA-bound transcription factors, and probably represent a general mechanism of transcriptional regulation. ..
- Peng C, Yajima H, Burns C, Zon L, Sisodia S, Pfaff S, et al. Notch and MAML signaling drives Scl-dependent interneuron diversity in the spinal cord. Neuron. 2007;53:813-27 pubmed..Thus, our study provides insight into the cell-extrinsic signaling that controls combinatorial transcription factor profiles involved in regulating the process of interneuron subtype diversification. ..
- Davis S, Camper S. Noggin regulates Bmp4 activity during pituitary induction. Dev Biol. 2007;305:145-60 pubmed..This work demonstrates the importance of attenuating the activity of Bmp signaling during pituitary induction in order to maintain the proper balance of signaling factors necessary for pituitary organogenesis. ..
- Zhao L, Zevallos S, Rizzoti K, Jeong Y, Lovell Badge R, Epstein D. Disruption of SoxB1-dependent Sonic hedgehog expression in the hypothalamus causes septo-optic dysplasia. Dev Cell. 2012;22:585-96 pubmed publisher..These data indicate that reduced levels of Shh expression in the hypothalamus cause SOD. ..
- Huber A, Kania A, Tran T, Gu C, De Marco Garcia N, Lieberam I, et al. Distinct roles for secreted semaphorin signaling in spinal motor axon guidance. Neuron. 2005;48:949-64 pubmed..Thus, Sema3A-Npn-1 and Sema3F-Npn-2 signaling control distinct steps of motor axon growth and guidance during the formation of spinal motor connections. ..
- Lieberam I, Agalliu D, Nagasawa T, Ericson J, Jessell T. A Cxcl12-CXCR4 chemokine signaling pathway defines the initial trajectory of mammalian motor axons. Neuron. 2005;47:667-79 pubmed..In its absence, these neurons adopt a dMN-like trajectory, despite preservation of their vMN transcriptional identity. Thus, the status of Cxcr4 signaling helps to determine the initial axonal trajectory of mammalian motor neurons. ..
- Seidah N, Barale J, Marcinkiewicz M, Mattei M, Day R, Chretien M. The mouse homeoprotein mLIM-3 is expressed early in cells derived from the neuroepithelium and persists in adult pituitary. DNA Cell Biol. 1994;13:1163-80 pubmed..These data suggest a potential role for mLIM-3 in the transcriptional regulation of certain genes during morphogenesis and/or maintenance of the differentiated state of the pituitary, motor neurons, and pineal gland. ..
- Savage J, Mullen R, Sloop K, Colvin S, Camper S, Franklin C, et al. Transgenic mice expressing LHX3 transcription factor isoforms in the pituitary: effects on the gonadotrope axis and sex-specific reproductive disease. J Cell Physiol. 2007;212:105-17 pubmedThe LHX3 transcription factor plays critical roles in pituitary and nervous system development. Mutations in the human LHX3 gene cause severe hormone deficiency diseases...
- Zhao Y, Morales D, Hermesz E, Lee W, Pfaff S, Westphal H. Reduced expression of the LIM-homeobox gene Lhx3 impairs growth and differentiation of Rathke's pouch and increases cell apoptosis during mouse pituitary development. Mech Dev. 2006;123:605-13 pubmed..The LIM-homeodoamin protein Lhx3 has previously been shown to play an essential role in the growth of Rathke's pouch, a primordium of the anterior ..
- Sloop K, Meier B, Bridwell J, Parker G, Schiller A, Rhodes S. Differential activation of pituitary hormone genes by human Lhx3 isoforms with distinct DNA binding properties. Mol Endocrinol. 1999;13:2212-25 pubmedb>Lhx3 is a LIM homeodomain transcription factor essential for pituitary development and motor neuron specification in mice...
- Charles M, Suh H, Hjalt T, Drouin J, Camper S, Gage P. PITX genes are required for cell survival and Lhx3 activation. Mol Endocrinol. 2005;19:1893-903 pubmed..knockouts of Pitx1 and Pitx2 exhibit severe pituitary hypoplasia and fail to express the transcription factor LHX3. This indicates that these PITX genes are upstream of Lhx3 and have compensatory roles during development...
- Bhati M, Lee C, Nancarrow A, Lee M, Craig V, Bach I, et al. Implementing the LIM code: the structural basis for cell type-specific assembly of LIM-homeodomain complexes. EMBO J. 2008;27:2018-29 pubmed publisher..In the ventral spinal cord, the binary LIM homeobox protein 3 (Lhx3)/LIM domain-binding protein 1 (Ldb1) complex specifies the formation of V2 interneurons...
- De Marco Garcia N, Jessell T. Early motor neuron pool identity and muscle nerve trajectory defined by postmitotic restrictions in Nkx6.1 activity. Neuron. 2008;57:217-31 pubmed publisher..Our findings provide genetic evidence that neurons within motor pools possess an early transcriptional identity that controls target muscle specificity. ..
- Briscoe J, Sussel L, Serup P, HARTIGAN O CONNOR D, Jessell T, Rubenstein J, et al. Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling. Nature. 1999;398:622-7 pubmed..Thus, Nkx2.2 has an essential role in interpreting graded Shh signals and selecting neuronal identity. ..
- Brinkmeier M, Potok M, Davis S, Camper S. TCF4 deficiency expands ventral diencephalon signaling and increases induction of pituitary progenitors. Dev Biol. 2007;311:396-407 pubmed..Thus, TCF4 is necessary both intrinsically and extrinsically to Rathke's pouch to ensure the proper growth of the pituitary gland. ..
- Ericson J, Norlin S, Jessell T, Edlund T. Integrated FGF and BMP signaling controls the progression of progenitor cell differentiation and the emergence of pattern in the embryonic anterior pituitary. Development. 1998;125:1005-15 pubmed..BMPs, in contrast, have no apparent effect on cell proliferation but instead appear to act with FGFs to control the initial selection of thyrotroph and corticotroph progenitor identity. ..
- Savage J, Hunter C, Clark Sturm S, Jacob T, Pfaeffle R, Rhodes S. Mutations in the LHX3 gene cause dysregulation of pituitary and neural target genes that reflect patient phenotypes. Gene. 2007;400:44-51 pubmedThe LHX3 LIM-homeodomain transcription factor is required for correct development of the mammalian pituitary gland and spinal motoneurons...
- Netchine I, Sobrier M, Krude H, Schnabel D, Maghnie M, Marcos E, et al. Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet. 2000;25:182-6 pubmed..We have isolated LHX3, a gene involved in a new syndrome, using a candidate-gene approach developed on the basis of documented pituitary ..
- Simon R, Lufkin T. Postnatal lethality in mice lacking the Sax2 homeobox gene homologous to Drosophila S59/slouch: evidence for positive and negative autoregulation. Mol Cell Biol. 2003;23:9046-60 pubmed..Intriguingly, our studies also demonstrated a striking autoregulation of the Sax2 gene in both positive- and negative-feedback mechanisms depending on the specific cell type expressing Sax2. ..
- Suh H, Gage P, Drouin J, Camper S. Pitx2 is required at multiple stages of pituitary organogenesis: pituitary primordium formation and cell specification. Development. 2002;129:329-37 pubmed..The model developed for PITX gene function in pituitary development provides a better understanding of the etiology of Rieger syndrome and may extend to other PITX-sensitive developmental processes. ..
- Ji S, Zhuang B, Falco C, Schneider A, Schuster Gossler K, Gossler A, et al. Mesodermal and neuronal retinoids regulate the induction and maintenance of limb innervating spinal motor neurons. Dev Biol. 2006;297:249-61 pubmed..These findings suggest that during embryogenesis, mesodermal and neuronal retinoids act coordinately to establish and maintain appropriate cohorts of spinal motor neurons that innervate target muscles in the limb. ..
- Chen J, Wichterle H. Apoptosis of limb innervating motor neurons and erosion of motor pool identity upon lineage specific dicer inactivation. Front Neurosci. 2012;6:69 pubmed publisher..Furthermore, it leads to defects in motor pool identity specification. Thus, our results indicate that miRNAs are an integral part of the genetic program controlling motor neuron survival and acquisition of subtype specific properties. ..
- Lee S, Lee B, Lee J, Lee S. Retinoid signaling and neurogenin2 function are coupled for the specification of spinal motor neurons through a chromatin modifier CBP. Neuron. 2009;62:641-54 pubmed publisher..Our study uncovers the mechanism by which extrinsic RA-signal and intrinsic transcription factor Ngn2 cooperate for cell fate specification through their synergistic activity to trigger transcriptionally active chromatin. ..
- Joshi K, Lee S, Lee B, Lee J, Lee S. LMO4 controls the balance between excitatory and inhibitory spinal V2 interneurons. Neuron. 2009;61:839-51 pubmed publisher..In the spinal cord, LMO4 induces GABAergic V2b-interneurons in collaboration with SCL and inhibits Lhx3 from generating glutamatergic V2a-interneuons...
- Davis S, Mortensen A, Keisler J, Zacharias A, Gage P, Yamamura K, et al. ?-catenin is required in the neural crest and mesencephalon for pituitary gland organogenesis. BMC Dev Biol. 2016;16:16 pubmed publisher..catenin in the Wnt1 expression domain, including the neural crest, plays a critical role in regulation of pituitary gland growth, development, and vascularization. ..
- Lu Q, Sun T, Zhu Z, Ma N, Garcia M, Stiles C, et al. Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell. 2002;109:75-86 pubmed..Neither Olig gene is required for astrocytes. These findings, together with fate mapping analysis of Olig-expressing cells, indicate that oligodendrocytes are derived from Olig-specified progenitors that give rise also to neurons. ..
- Tremblay J, Lanctot C, Drouin J. The pan-pituitary activator of transcription, Ptx1 (pituitary homeobox 1), acts in synergy with SF-1 and Pit1 and is an upstream regulator of the Lim-homeodomain gene Lim3/Lhx3. Mol Endocrinol. 1998;12:428-41 pubmed..Interestingly, the only other gene found to be highly dependent on Ptx1 for expression was the gene for the Lim3/Lhx3 transcription factor...
- Seo S, Lee B, Lee S. Critical Roles of the LIM Domains of Lhx3 in Recruiting Coactivators to the Motor Neuron-Specifying Isl1-Lhx3 Complex. Mol Cell Biol. 2015;35:3579-89 pubmed publisherDuring spinal cord development, the LIM domains of the LIM homeodomain factor Lhx3 bind to either the LIM cofactor nuclear LIM interactor (NLI) or another LIM homeodomain factor, Isl1, assembling the tetrameric V2 interneuron-specifying ..
- Heydeck W, Liu A. PCP effector proteins inturned and fuzzy play nonredundant roles in the patterning but not convergent extension of mammalian neural tube. Dev Dyn. 2011;240:1938-48 pubmed publisher..Finally, we show in Intu; Fuz double mutants that the lack of convergent extension and more severe patterning defects in Intu and Fuz mutants does not result from a functional redundancy between these two proteins. ..
- Cepeda Nieto A, Pfaff S, Varela Echavarria A. Homeodomain transcription factors in the development of subsets of hindbrain reticulospinal neurons. Mol Cell Neurosci. 2005;28:30-41 pubmed..neurons in chick and mouse embryos combined with immunostaining for the homeodomain factors Lhx1/Lhx5, Lhx3/Lhx4, and Chx10 have defined transcriptional codes that label subsets of neurons with different axon projection ..
- Huangfu D, Anderson K. Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci U S A. 2005;102:11325-30 pubmed
- Cha K, Douglas K, Potok M, Liang H, Jones S, Camper S. WNT5A signaling affects pituitary gland shape. Mech Dev. 2004;121:183-94 pubmed..This study suggests that the primary role of Wnt5a in the developing pituitary gland is in establishment of the shape of the gland. ..
- Eggenschwiler J, Espinoza E, Anderson K. Rab23 is an essential negative regulator of the mouse Sonic hedgehog signalling pathway. Nature. 2001;412:194-8 pubmed..The data indicate that dorsalizing signals activate transcription of Rab23 in order to silence the Shh pathway in dorsal neural cells. ..
- Liang X, Song M, Xu Z, Lanuza G, Liu Y, Zhuang T, et al. Isl1 is required for multiple aspects of motor neuron development. Mol Cell Neurosci. 2011;47:215-22 pubmed publisher..In addition, Isl1 is required for survival of cranial ganglia neurons. ..
- Gage P, Suh H, Camper S. Dosage requirement of Pitx2 for development of multiple organs. Development. 1999;126:4643-51 pubmed..This allelic series establishes that Pitx2 is required for the development of mulitple organs in a dosage-sensitive manner. ..
- Lee S, Jurata L, Nowak R, Lettieri K, Kenny D, Pfaff S, et al. The LIM domain-only protein LMO4 is required for neural tube closure. Mol Cell Neurosci. 2005;28:205-14 pubmed..LMO4 is also expressed in Schwann cell progenitors after these contact neurites, a process mediated in part by neuregulin (Nrg). ..
- Raetzman L, Ward R, Camper S. Lhx4 and Prop1 are required for cell survival and expansion of the pituitary primordia. Development. 2002;129:4229-39 pubmed..results from increased cell death and that the reduced differentiation is attributable to a temporal shift in Lhx3 activation...
- Scardigli R, Schuurmans C, Gradwohl G, Guillemot F. Crossregulation between Neurogenin2 and pathways specifying neuronal identity in the spinal cord. Neuron. 2001;31:203-17 pubmed..Thus, neuronal differentiation involves crossregulatory interactions between a bHLH-driven program of neurogenesis and genetic pathways specifying progenitor and neuronal identity in the spinal cord. ..
- Thaler J, Koo S, Kania A, Lettieri K, Andrews S, Cox C, et al. A postmitotic role for Isl-class LIM homeodomain proteins in the assignment of visceral spinal motor neuron identity. Neuron. 2004;41:337-50 pubmed..Thus, an early phase of high Isl expression and activity in newly generated motor neurons permits the diversification of visceral and somatic motor neuron subtypes in the developing spinal cord. ..
- Yan Y, Wladyka C, Fujii J, Sockanathan S. Prdx4 is a compartment-specific H2O2 sensor that regulates neurogenesis by controlling surface expression of GDE2. Nat Commun. 2015;6:7006 pubmed publisher..Thus, Prdx4 oxidative activity acts as a sensor to directly couple neuronal differentiation with redox environments in the ER. ..
- Amin N, Bai G, Klug J, Bonanomi D, Pankratz M, Gifford W, et al. Loss of motoneuron-specific microRNA-218 causes systemic neuromuscular failure. Science. 2015;350:1525-9 pubmed publisher..Thus, the set of messenger RNAs targeted by miR-218, designated TARGET(218), defines a neuronal gene network that is selectively tuned down in motoneurons to prevent neuromuscular failure and neurodegeneration. ..
- Crone S, Quinlan K, Zagoraiou L, Droho S, Restrepo C, Lundfald L, et al. Genetic ablation of V2a ipsilateral interneurons disrupts left-right locomotor coordination in mammalian spinal cord. Neuron. 2008;60:70-83 pubmed publisher..Our findings imply that the neural substrate for left-right coordination consists of at least two components; commissural neurons and a class of ipsilateral interneurons that activate commissural pathways. ..
- Al Mosawie A, Wilson J, Brownstone R. Heterogeneity of V2-derived interneurons in the adult mouse spinal cord. Eur J Neurosci. 2007;26:3003-15 pubmed..During spinal cord development, expression of Lhx3 in the absence of Isl1 specifies a V2 interneuronal fate...
- Gadd M, Jacques D, Nisevic I, Craig V, Kwan A, Guss J, et al. A structural basis for the regulation of the LIM-homeodomain protein islet 1 (Isl1) by intra- and intermolecular interactions. J Biol Chem. 2013;288:21924-35 pubmed publisher..In Isl1, the C-terminal region also contains the LIM homeobox 3 (Lhx3)-binding domain (LBD), which interacts with the LIM domains of Lhx3...
- Wang W, Grimmer J, Van De Water T, Lufkin T. Hmx2 and Hmx3 homeobox genes direct development of the murine inner ear and hypothalamus and can be functionally replaced by Drosophila Hmx. Dev Cell. 2004;7:439-53 pubmed
- Sloop K, Showalter A, Von Kap Herr C, Pettenati M, Rhodes S. Analysis of the human LHX3 neuroendocrine transcription factor gene and mapping to the subtelomeric region of chromosome 9. Gene. 2000;245:237-43 pubmedThe Lhx3 LIM homeodomain transcription factor is critical to pituitary organogenesis and motor neuron development. We determined the genomic structure and chromosomal localization of human LHX3...
- Wang L, Sharma K, Deng H, Siddique T, Grisotti G, Liu E, et al. Restricted expression of mutant SOD1 in spinal motor neurons and interneurons induces motor neuron pathology. Neurobiol Dis. 2008;29:400-8 pubmed..Mouse models similar to the one presented here will be valuable for spatially and temporally controlling expression of mutant genes involved in neurodegenerative diseases. ..
- Repetto E, Briata P, Kuziner N, Harfe B, McManus M, Gherzi R, et al. Let-7b/c enhance the stability of a tissue-specific mRNA during mammalian organogenesis as part of a feedback loop involving KSRP. PLoS Genet. 2012;8:e1002823 pubmed publisher..Our study unveils a functional crosstalk between miRNA- and AMD-dependent gene regulation during mammalian organogenesis events. ..
- Merchant M, Evangelista M, Luoh S, Frantz G, Chalasani S, Carano R, et al. Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus. Mol Cell Biol. 2005;25:7054-68 pubmed..These results show that the mFu homologue is not required for Hh signaling during embryonic development but is required for proper postnatal development, possibly by regulating the CSF homeostasis or ciliary function. ..
- Hoover A, Wynkoop A, Zeng H, Jia J, Niswander L, Liu A. C2cd3 is required for cilia formation and Hedgehog signaling in mouse. Development. 2008;135:4049-58 pubmed publisher..Interestingly, the human ortholog for this gene lies in proximity to the critical regions of Meckel-Gruber syndrome 2 (MKS2) and Joubert syndrome 2 (JBTS2), making it a potential candidate for these two human genetic disorders. ..
- Kim Y, Lim S, Ha T, Song Y, Sohn Y, Park D, et al. The LIM protein complex establishes a retinal circuitry of visual adaptation by regulating Pax6 ?-enhancer activity. elife. 2017;6: pubmed publisher..growth factor ß1-induced transcript 1 protein (Tgfb1i1) interacts with the LIM domain transcription factors Lhx3 and Isl1 to inhibit the ?-enhancer in the post-natal mouse retina...