Genomes and Genes
Gene Symbol: Alx4
Description: aristaless-like homeobox 4
Alias: lst, homeobox protein aristaless-like 4, ALX-4, Aristaless-like 4, Strong's luxoid, aristaless 4
- Lallemand Y, Nicola M, Ramos C, Bach A, Cloment C, Robert B. Analysis of Msx1; Msx2 double mutants reveals multiple roles for Msx genes in limb development. Development. 2005;132:3003-14 pubmed..This results in a major outgrowth of the mesenchyme anteriorly, which nevertheless maintains a posterior identity, and leads to formation of extra digits. These defects are interpreted in the context of an impairment of Bmp signalling. ..
- Kuijper S, Beverdam A, Kroon C, Brouwer A, Candille S, Barsh G, et al. Genetics of shoulder girdle formation: roles of Tbx15 and aristaless-like genes. Development. 2005;132:1601-10 pubmed..We have studied the impact of Tbx15, Gli3, Alx4 and related genes on formation of the skeletal elements of the mouse shoulder and pelvic girdles...
- Yamada R, Mizutani Koseki Y, Koseki H, Takahashi N. Requirement for Mab21l2 during development of murine retina and ventral body wall. Dev Biol. 2004;274:295-307 pubmed..Our results reveal that Mab21l2 plays crucial roles in retina and in ventral body wall formation. ..
- te Welscher P, Fernandez Teran M, Ros M, Zeller R. Mutual genetic antagonism involving GLI3 and dHAND prepatterns the vertebrate limb bud mesenchyme prior to SHH signaling. Genes Dev. 2002;16:421-6 pubmed..dHAND, in turn, excludes anterior genes such as Gli3 and Alx4 from posterior mesenchyme...
- Sun X, Mariani F, Martin G. Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature. 2002;418:501-8 pubmed..In the complete absence of both FGF4 and FGF8 activities, limb development fails. We present a model to explain how the mutant phenotypes arise from FGF-mediated effects on limb bud size and cell survival. ..
- Sagai T, Masuya H, Tamura M, Shimizu K, Yada Y, Wakana S, et al. Phylogenetic conservation of a limb-specific, cis-acting regulator of Sonic hedgehog ( Shh). Mamm Genome. 2004;15:23-34 pubmed..Absence of the conserved sequence in limbless reptiles and amphibians and a cis- trans test using the Hx and Shh KO alleles suggest that the sequence is a cis-acting regulator that controls the polarized expression of Shh...
- te Welscher P, Zuniga A, Kuijper S, Drenth T, Goedemans H, Meijlink F, et al. Progression of vertebrate limb development through SHH-mediated counteraction of GLI3. Science. 2002;298:827-30 pubmed..Our genetic analysis indicates that SHH signaling counteracts GLI3-mediated repression of key regulator genes, cell survival, and distal progression of limb bud development. ..
- Wu Y, Badano J, McCaskill C, Vogel H, Potocki L, Shaffer L. Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome. Am J Hum Genet. 2000;67:1327-32 pubmed..Further sequence analysis demonstrated that the human orthologue (ALX4) of the mouse Aristaless-like 4 gene (Alx4) is contained within this 11p clone...
- Galli A, Robay D, Osterwalder M, Bao X, Bénazet J, Tariq M, et al. Distinct roles of Hand2 in initiating polarity and posterior Shh expression during the onset of mouse limb bud development. PLoS Genet. 2010;6:e1000901 pubmed publisher..Our study uncovers essential components of the transcriptional machinery and key interactions that set-up limb bud asymmetry upstream of establishing the SHH signaling limb bud organizer. ..
- Liu N, Barbosa A, Chapman S, Bezprozvannaya S, Qi X, Richardson J, et al. DNA binding-dependent and -independent functions of the Hand2 transcription factor during mouse embryogenesis. Development. 2009;136:933-42 pubmed publisher..These findings suggest that Hand2 regulates tissue growth and development in vivo through DNA binding-dependent and -independent mechanisms. ..
- Qu S, Tucker S, Ehrlich J, Levorse J, Flaherty L, Wisdom R, et al. Mutations in mouse Aristaless-like4 cause Strong's luxoid polydactyly. Development. 1998;125:2711-21 pubmed..Integration of the lst genetic and physical maps suggested the mouse Aristaless-like4 (Alx4) gene, which encodes a paired-type homeodomain protein that plays a role in limb patterning, as a strong molecular ..
- Zhao H, Oka K, Bringas P, Kaartinen V, Chai Y. TGF-beta type I receptor Alk5 regulates tooth initiation and mandible patterning in a type II receptor-independent manner. Dev Biol. 2008;320:19-29 pubmed publisher..in early mandible patterning and altered expression of key patterning genes including Msx1, Bmp4, Bmp2, Pax9, Alx4, Lhx6/7 and Gsc...
- Chan D, Laufer E, Tabin C, Leder P. Polydactylous limbs in Strong's Luxoid mice result from ectopic polarizing activity. Development. 1995;121:1971-8 pubmed..We suggest that the 1st gene product is involved in anteroposterior axis formation during normal limb development. ..
- Forsthoefel P. Responses to selection for plus and minus modifiers of some effects of Strong's luxoid gene on the mouse skeleton. Teratology. 1968;1:339-51 pubmed
- Aggarwal V, Carpenter C, Freyer L, Liao J, Petti M, Morrow B. Mesodermal Tbx1 is required for patterning the proximal mandible in mice. Dev Biol. 2010;344:669-81 pubmed publisher..5. This occurs without significant changes in cell proliferation or apoptosis at the same stage. Our results elucidate a new function for the non-neural crest core mesoderm and specifically, mesodermal Tbx1, in shaping the lower jaw. ..
- Peichel C, Kozak C, Luyten F, Vogt T. Evaluation of mouse Sfrp3/Frzb1 as a candidate for the lst, Ul, and Far mutants on chromosome 2. Mamm Genome. 1998;9:385-7 pubmed
- Goodrich L, Johnson R, Milenkovic L, McMahon J, Scott M. Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog. Genes Dev. 1996;10:301-12 pubmed..As in flies, mouse ptc transcription appears to be indicative of hedgehog signal reception. The results support the existence of a conserved signaling pathway used for pattern formation in insects and mammals. ..
- Zhulyn O, Hui C. Sufu and Kif7 in limb patterning and development. Dev Dyn. 2015;244:468-78 pubmed publisher..Together, our findings demonstrate that perturbations of Sufu and Kif7 affect Gli activity and recapitulate the full spectrum of vertebrate limb defects, ranging from severe truncation to polydactyly. ..
- Curtain M, Heffner C, Maddox D, Gudis P, Donahue L, Murray S. A novel allele of Alx4 results in reduced Fgf10 expression and failure of eyelid fusion in mice. Mamm Genome. 2015;26:173-80 pubmed publisher..We have identified a novel spontaneous allele of Alx4 that displays EOB, in addition to polydactyly and cranial malformations...
- Garg A, Bansal M, Gotoh N, Feng G, Zhong J, Wang F, et al. Alx4 relays sequential FGF signaling to induce lacrimal gland morphogenesis. PLoS Genet. 2017;13:e1007047 pubmed publisher..of Sox10-expressing neural crests, Shp2 is also required for expression of the homeodomain transcription factor Alx4, which directly controls Fgf10 expression in the periocular mesenchyme that is necessary for lacrimal gland ..
- He F, Soriano P. A critical role for PDGFR? signaling in medial nasal process development. PLoS Genet. 2013;9:e1003851 pubmed publisher..We thus establish PDGFR? as a novel regulator of MNP development and elucidate the roles of its downstream signaling pathways at cellular and molecular levels. ..
- Boras K, Hamel P. Alx4 binding to LEF-1 regulates N-CAM promoter activity. J Biol Chem. 2002;277:1120-7 pubmedDuring murine embryogenesis, expression of the paired-like homeodomain protein Alx4 is restricted to tissues whose development depends on the expression of lymphoid enhancer factor-1 (LEF-1)...
- Ota M, Loebel D, O Rourke M, Wong N, Tsoi B, Tam P. Twist is required for patterning the cranial nerves and maintaining the viability of mesodermal cells. Dev Dyn. 2004;230:216-28 pubmed
- Capellini T, Handschuh K, Quintana L, Ferretti E, Di Giacomo G, Fantini S, et al. Control of pelvic girdle development by genes of the Pbx family and Emx2. Dev Dyn. 2011;240:1173-89 pubmed publisher..Lastly, we identify potential Pbx1-Emx2-regulated enhancers for Tbx15, Prrx1, and Pax1, using bioinformatics analyses. ..
- Krawchuk D, Weiner S, Chen Y, Lu B, Costantini F, Behringer R, et al. Twist1 activity thresholds define multiple functions in limb development. Dev Biol. 2010;347:133-46 pubmed publisher..Our data support a model whereby multiple Twist1 activity thresholds contribute to early limb bud patterning, and suggest how particular combinations of skeletal defects result from differing amounts of Twist1 activity. ..
- Lettice L, Hecksher Sørensen J, Hill R. The dominant hemimelia mutation uncouples epithelial-mesenchymal interactions and disrupts anterior mesenchyme formation in mouse hindlimbs. Development. 1999;126:4729-36 pubmed..The Dh gene functions in the initial stages of limb development and we suggest that these initial roles are linked to mechanisms that pattern gene expression in the AER. ..
- Depew M, Lufkin T, Rubenstein J. Specification of jaw subdivisions by Dlx genes. Science. 2002;298:381-5 pubmed..We suggest that nested Dlx expression in the arches patterns their proximodistal axes. Evolutionary acquisition and subsequent refinement of jaws may have been dependent on modification of Dlx expression. ..
- Hong M, Schachter K, Jiang G, Krauss R. Neogenin regulates Sonic Hedgehog pathway activity during digit patterning. Dev Dyn. 2012;241:627-37 pubmed publisher..Furthermore, embryo fibroblasts from Neo1 mutant mice are sensitized to SHH pathway activation in vitro. Our findings indicate that neogenin regulates SHH signaling in the limb bud to achieve proper digit patterning. ..
- Capellini T, Vaccari G, Ferretti E, Fantini S, He M, Pellegrini M, et al. Scapula development is governed by genetic interactions of Pbx1 with its family members and with Emx2 via their cooperative control of Alx1. Development. 2010;137:2559-69 pubmed publisher..Our results establish an essential role for Pbx1 in genetic interactions with its family members and with Emx2 and delineate novel regulatory networks in shoulder girdle development. ..
- Ko S, Chung I, Xu X, Oka S, Zhao H, Cho E, et al. Smad4 is required to regulate the fate of cranial neural crest cells. Dev Biol. 2007;312:435-47 pubmed..Taken together, our data show that TGF-beta/BMP signals rely on Smad-dependent pathways in the ectomesenchyme to mediate epithelial-mesenchymal interactions that control craniofacial organogenesis...
- Matsumaru D, Haraguchi R, Moon A, Satoh Y, Nakagata N, Yamamura K, et al. Genetic analysis of the role of Alx4 in the coordination of lower body and external genitalia formation. Eur J Hum Genet. 2014;22:350-7 pubmed publisher..Naturally occurring mutations in Aristaless-like 4 (Alx4, Strong's luxoid: Alx4Lst) have ventral body wall and pelvic girdle abnormalities...
- Zhang Z, Yu X, Zhang Y, Geronimo B, Lovlie A, Fromm S, et al. Targeted misexpression of constitutively active BMP receptor-IB causes bifurcation, duplication, and posterior transformation of digit in mouse limb. Dev Biol. 2000;220:154-67 pubmed..In addition, BMPR-IB may represent a critical component in the Shh/FGF4 feedback loop by regulating Gremlin expression. ..
- Moribe H, Takagi T, Kondoh H, Higashi Y. Suppression of polydactyly of the Gli3 mutant (extra toes) by deltaEF1 homozygous mutation. Dev Growth Differ. 2000;42:367-76 pubmed..The data suggest the possibility that the extent of Hoxd13 expression along the distal margin of the limb bud is determinative in defining the digit number. ..
- Makino S, Zhulyn O, Mo R, Puviindran V, Zhang X, Murata T, et al. T396I mutation of mouse Sufu reduces the stability and activity of Gli3 repressor. PLoS ONE. 2015;10:e0119455 pubmed publisher..This implies a novel Sufu-mediated mechanism in which Gli2 activator and Gli3 repressor are differentially regulated. ..
- Boras Granic K, Grosschedl R, Hamel P. Genetic interaction between Lef1 and Alx4 is required for early embryonic development. Int J Dev Biol. 2006;50:601-10 pubmed..We determined previously that the mesenchymally restricted, paired-like homeodomain protein Aristaless-like 4 (Alx4) interacts with Lef1 and together alters promoter activity of candidate genes...
- O Rourke M, Soo K, Behringer R, Hui C, Tam P. Twist plays an essential role in FGF and SHH signal transduction during mouse limb development. Dev Biol. 2002;248:143-56 pubmed..SHH signalling in the limb bud mesenchyme, the down-regulation of Bmp4 in the apical ectoderm, the absence of Alx3, Alx4, Pax1, and Pax3 activity in the mesenchyme, and a reduced potency of the limb bud tissues to differentiate into ..
- Li C, Xu X, Nelson D, Williams T, Kuehn M, Deng C. FGFR1 function at the earliest stages of mouse limb development plays an indispensable role in subsequent autopod morphogenesis. Development. 2005;132:4755-64 pubmed..of a number of genes involved in apoptosis and digit patterning, including increased expression of Bmp4, Dkk1 and Alx4, and downregulation of MKP3...
- Liu W, Selever J, Murali D, Sun X, Brugger S, Ma L, et al. Threshold-specific requirements for Bmp4 in mandibular development. Dev Biol. 2005;283:282-93 pubmed..Lastly, we provide evidence that Prx homeobox genes repress expression of an Msx2 transgene, previously shown to be Bmp4-responsive, revealing a mechanism for differential regulation of Msx1 and Msx2 by Bmp signaling. ..
- Beverdam A, Meijlink F. Expression patterns of group-I aristaless-related genes during craniofacial and limb development. Mech Dev. 2001;107:163-7 pubmed
- Hudson R, Taniguchi Sidle A, Boras K, Wiggan O, Hamel P. Alx-4, a transcriptional activator whose expression is restricted to sites of epithelial-mesenchymal interactions. Dev Dyn. 1998;213:159-69 pubmed..Taken together, our results demonstrate that Alx-4 is a potent transcriptional activator that is expressed at sites of epithelial-mesenchymal interactions during murine embryonic development. ..
- Vogt T, Leder P. Polydactyly in the Strong's luxoid mouse is suppressed by limb deformity alleles. Dev Genet. 1996;19:33-42 pubmed..analysis to the process of limb development by studying two mouse mutants, limb deformity (ld) and Strong's luxoid (lst). These mutations confer contrasting phenotypic alterations to the anteroposterior limb pattern...
- Li D, Sakuma R, Vakili N, Mo R, Puviindran V, Deimling S, et al. Formation of proximal and anterior limb skeleton requires early function of Irx3 and Irx5 and is negatively regulated by Shh signaling. Dev Cell. 2014;29:233-40 pubmed publisher..Our data provide genetic evidence supporting the concept of early specification and progressive determination of anterior limb pattern. ..
- Johnson D. The interfrontal bone and mutant genes in the mouse. J Anat. 1976;121:507-13 pubmed..All genes reviewed which increase the incidence of the interfrontal bone and affect the neural tube also change the proportions of the adult skull. ..
- Zhang Z, Verheyden J, Hassell J, Sun X. FGF-regulated Etv genes are essential for repressing Shh expression in mouse limb buds. Dev Cell. 2009;16:607-13 pubmed publisher..This finding elucidates a novel aspect of the mechanism coordinating limb development along the A-P and P-D axes...
- Verheyden J, Lewandoski M, Deng C, Harfe B, Sun X. Conditional inactivation of Fgfr1 in mouse defines its role in limb bud establishment, outgrowth and digit patterning. Development. 2005;132:4235-45 pubmed..Our study of these two Fgfr1 conditional mutants has elucidated the multiple roles of FGFR1 in limb bud establishment, growth and patterning. ..
- Bowers M, Eng L, Lao Z, Turnbull R, Bao X, Riedel E, et al. Limb anterior-posterior polarity integrates activator and repressor functions of GLI2 as well as GLI3. Dev Biol. 2012;370:110-24 pubmed publisher..Taken together, our data suggest that establishment of a complete range of AP positional identities in the limb requires integration of the spatial distribution, timing, and dosage of GLI2 and GLI3 activators and repressors. ..
- Antonopoulou I, Mavrogiannis L, Wilkie A, Morriss Kay G. Alx4 and Msx2 play phenotypically similar and additive roles in skull vault differentiation. J Anat. 2004;204:487-99 pubmedb>Alx4 and Msx2 encode homeodomain-containing transcription factors that show a clear functional overlap...
- Vivatbutsiri P, Ichinose S, Hytönen M, Sainio K, Eto K, Iseki S. Impaired meningeal development in association with apical expansion of calvarial bone osteogenesis in the Foxc1 mutant. J Anat. 2008;212:603-11 pubmed publisher..These results suggest that there is a close association between meningeal development and the apical growth of the skull bones. ..
- Britanova O, Depew M, Schwark M, Thomas B, Miletich I, Sharpe P, et al. Satb2 haploinsufficiency phenocopies 2q32-q33 deletions, whereas loss suggests a fundamental role in the coordination of jaw development. Am J Hum Genet. 2006;79:668-78 pubmed..of expression of three genes implicated in the regulation of craniofacial development in humans and mice: Pax9, Alx4, and Msx1...
- Hide T, Hatakeyama J, Kimura Yoshida C, Tian E, Takeda N, Ushio Y, et al. Genetic modifiers of otocephalic phenotypes in Otx2 heterozygous mutant mice. Development. 2002;129:4347-57 pubmed..Furthermore, these experiments offer a powerful approach with respect to identification and characterization of candidate genes that may contribute to human agnathia-holoprosencephaly complex diseases. ..
- Yada Y, Makino S, Chigusa Ishiwa S, Shiroishi T. The mouse polydactylous mutation, luxate (lx), causes anterior shift of the anteroposterior border in the developing hindlimb bud. Int J Dev Biol. 2002;46:975-82 pubmed..Conversely, the expression domains of anterior mesenchymal markers such as Gli3and Alx4 decreased in size. Thus, ectopic Shh is not a primary defect of the lx mutation...
- Dunn N, Winnier G, Hargett L, Schrick J, Fogo A, Hogan B. Haploinsufficient phenotypes in Bmp4 heterozygous null mice and modification by mutations in Gli3 and Alx4. Dev Biol. 1997;188:235-47 pubmed..a deletion mutation involving a gene encoding a zinc-finger protein related to Drosophila cubitus interruptus, and Alx4(tm1rwm), a targeted null mutation in a gene encoding a paired class homeoprotein related to Drosophila aristaless...
- Loebel D, O Rourke M, Steiner K, Banyer J, Tam P. Isolation of differentially expressed genes from wild-type and Twist mutant mouse limb buds. Genesis. 2002;33:103-13 pubmed..We show that the aristaless-like transcription factors, Alx3 and Alx4 are downregulated in the Twist(-/-) mutant and may be potential targets of Twist...
- Hansen G, Skapura D, Justice M. Genetic profile of insertion mutations in mouse leukemias and lymphomas. Genome Res. 2000;10:237-43 pubmed
- Minoux M, Antonarakis G, Kmita M, Duboule D, Rijli F. Rostral and caudal pharyngeal arches share a common neural crest ground pattern. Development. 2009;136:637-45 pubmed publisher..These results provide insights into how facial and throat structures are assembled during development, and have implications for the evolution of the pharyngeal region of the vertebrate head. ..
- Manley N, Barrow J, Zhang T, Capecchi M. Hoxb2 and hoxb4 act together to specify ventral body wall formation. Dev Biol. 2001;237:130-44 pubmed..5, before secondary body wall formation. Prior to this defect, both Alx3 and Alx4 were specifically down regulated in the most ventral part of the primary body wall in Hoxb4(PolII) mutants...
- Maas R, Elfering S, Glaser T, Jepeal L. Deficient outgrowth of the ureteric bud underlies the renal agenesis phenotype in mice manifesting the limb deformity (ld) mutation. Dev Dyn. 1994;199:214-28 pubmed..However, since ld transcripts can be detected in both metanephric mesenchyme and ureteric bud, the molecular basis for the deficiency in ureteric bud outgrowth could reside in either component. ..
- Forsthoefel P, Williams M. The effects of 5-fluorouracil and 5-fluorodeoxyuridine used alone and in combination with normal nucleic acid precursors on development of mice in lines selected for low and high expression of Strong's luxoid gene. Teratology. 1975;11:1-13 pubmed..The interactions of the teratogens with the major gene were inhibited by minus- and promoted by plus-modifying genes of 1st. The effects of the teratogenic treatments may be mediated by cell death. ..
- Wyngaarden L, Delgado Olguin P, Su I, Bruneau B, Hopyan S. Ezh2 regulates anteroposterior axis specification and proximodistal axis elongation in the developing limb. Development. 2011;138:3759-67 pubmed publisher..Ezh2 maintains the late phase of Hox gene expression and cell transposition experiments suggest that it regulates the plasticity with which cells respond to instructive positional cues. ..
- Lakhwani S, García Sanz P, Vallejo M. Alx3-deficient mice exhibit folic acid-resistant craniofacial midline and neural tube closure defects. Dev Biol. 2010;344:869-80 pubmed publisher..Thus, Alx3 emerges as a candidate gene for human neural tube defects and reveals the existence of induced transcription factor gene expression as a previously unknown mechanism by which folic acid prevents neural tube closure defects. ..
- Dunwoodie S, Henrique D, Harrison S, Beddington R. Mouse Dll3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo. Development. 1997;124:3065-76 pubmed..We hypothesise that Dll1 is involved in the release of cells from the precursor population and that Dll3 is required later to divert neurons along a specific differentiation pathway. ..
- Matsumaru D, Haraguchi R, Miyagawa S, Motoyama J, Nakagata N, Meijlink F, et al. Genetic analysis of Hedgehog signaling in ventral body wall development and the onset of omphalocele formation. PLoS ONE. 2011;6:e16260 pubmed publisher..of mouse mutants of Sonic hedgehog (Shh), GLI-Kruppel family member 3 (Gli3) and Aristaless-like homeobox 4 (Alx4)...
- Qu S, Tucker S, Zhao Q, DeCrombrugghe B, Wisdom R. Physical and genetic interactions between Alx4 and Cart1. Development. 1999;126:359-69 pubmedb>Alx4 and Cart1 are closely related members of the family of transcription factors that contain the paired-type homeodomain...
- Bildsoe H, Loebel D, Jones V, Chen Y, Behringer R, Tam P. Requirement for Twist1 in frontonasal and skull vault development in the mouse embryo. Dev Biol. 2009;331:176-88 pubmed publisher..In contrast, the formation of other mesodermal skeletal derivatives such as the occipital bones and most of the chondrocranium are not affected by the loss of Twist1 in the neural crest cells. ..
- Lu P, Yu Y, Perdue Y, Werb Z. The apical ectodermal ridge is a timer for generating distal limb progenitors. Development. 2008;135:1395-405 pubmed publisher..Taken together, we have uncovered a novel mechanism, whereby the AER regulates the number of autopod progenitors by determining the onset of their generation. ..
- Hayashi S, Akiyama R, Wong J, Tahara N, Kawakami H, Kawakami Y. Gata6-Dependent GLI3 Repressor Function is Essential in Anterior Limb Progenitor Cells for Proper Limb Development. PLoS Genet. 2016;12:e1006138 pubmed publisher..Both the genetic and biochemical data elucidates a novel mechanism by Gata6 to regulate GLI3R activities in the anterior limb progenitor cells to prevent polydactyly and attain proper development of the mammalian autopod. ..
- Selever J, Liu W, Lu M, Behringer R, Martin J. Bmp4 in limb bud mesoderm regulates digit pattern by controlling AER development. Dev Biol. 2004;276:268-79 pubmed..Our data show that Bmp4 in limb mesoderm regulates AER induction and maturation and implicate signaling from the AER in regulation of digit number and identity. ..