Alternative titles; symbols
HGNC Approved Gene Symbol: FMN1
Cytogenetic location: 15q13.3 Genomic coordinates (GRCh38) : 15:32,765,544-33,194,714 (from NCBI)
Formins, such as FMN1, are actin-nucleating proteins involved in cell polarity, cytokinesis, cell migration, and transcriptional activity (Hu et al., 2014)
Mutation at the mouse 'limb deformity' (ld) locus disrupts embryonic pattern formation, resulting in a reduction and fusion of the distal bones and digits of all limbs as well as variable incidence of renal aplasia. Woychik et al. (1990) characterized the ld locus at the molecular level and identified a complex gene which, because of its presumed role in the formation of limbs and kidneys, was designated formin.
Maas et al. (1991) described sequence and restriction-mapping data for a human genomic clone that contained 2 major human-mouse homology regions. They assigned the locus symbol LD to the human gene locus. They also demonstrated 2 frequently occurring DNA polymorphisms at the LD locus potentially useful for testing linkage to human syndromes that combine limb and renal abnormalities.
Vogt et al. (1993) showed that the large and complex LD gene has the capacity to generate a number of alternatively spliced mRNA transcripts encoding nuclear protein isoforms called formins. They made polyclonal antibodies to specific formin peptides and confirmed the authenticity of the reactivity of the antibodies, using cell lines derived from mice with molecularly defined mutations at the ld locus.
Zuniga et al. (1999) reported that the secreted bone morphogenetic protein (BMP) antagonist gremlin (GREM1; 603054) relays the Sonic hedgehog (SHH; 600725) signal from the polarizing region to the apical ectodermal ridge. Mesenchymal gremlin expression is lost in limb buds of mouse embryos homozygous for the ld mutation, which disrupts establishment of the Shh/Fgf4 (164980) feedback loop. Grafting gremlin-expressing cells into ld mutant limb buds rescued Fgf4 expression and restored the Shh/Fgf4 feedback loop. Analysis of Shh-null mutant embryos revealed that Shh signaling is required for maintenance of gremlin and Fmn1, the gene disrupted by the ld mutations. In contrast, Fmn1, gremlin, and Fgf4 activation were independent of Shh signaling. Zuniga et al. (1999) concluded that the study uncovered the cascade by which the SHH signal is relayed from the posterior mesenchyme to the apical ectodermal ridge and established that formin-dependent activation of the BMP antagonist gremlin is sufficient to induce FGF4 and establish the SHH/FGF4 feedback loop.
Using a yeast 2-hybrid system to analyze alpha-catenin (see 116805) binding partners, Kobielak et al. (2004) found direct interaction between alpha-catenin and formin in a mouse skin expression library. In addition, they found that formin nucleated the polymerization of unbranched actin (see 102610) filaments in vitro and functioned in vivo in alpha-catenin-dependent, radial actin cable formation.
Using yeast 2-hybrid and immunoprecipitation analyses, Hu et al. (2014) found that the mouse actin-binding proteins Flnb (603381) and Flna (300017) interacted directly with Fmn1. The filamins and Fmn1 colocalized in cytoplasm and, to a lesser extent, nucleus, and they were coexpressed in chondrocytes.
Wang et al. (1997) found that the mouse Fmn1 gene is very large, spanning 400 kb and comprising at least 24 exons. Wang et al. (1997) stated that some of the introns are very large, ranging more than 50 kb, and may play a role in transcriptional regulation.
Maas et al. (1991) showed by a combination of mouse/human somatic cell hybrid studies and in situ hybridization that the human LD gene is located on 15q13-q14. Both this and the beta-2-microglobulin gene (109700) are located on chromosome 2 in the mouse.
Richard et al. (1992) mapped the LD locus on chromosome 15, proximal to the gene for cardiac muscle alpha-actin (ACTC; 102540).
Richard et al. (1994) mapped 149 chromosome 15 loci, including those for 18 genes, 60 cDNA-derived sequence-tagged sites (STS), and 69 microsatellites by PCR with respect to chromosome breakpoints in 3 somatic cell hybrids retaining all or part of chromosome 15 and to a 10-Mb YAC contig. Chromosome 15 was divided into 5 regions, yielding an average resolution of more than 1 sequence tagged site per megabase. They mapped the FMN gene to their region I: 15pter-q14.
The murine 'limb deformity' (ld) locus is defined by several different noncomplementing mutant alleles which share a characteristic limb deformity and variably penetrant renal aplasia phenotype (Green, 1981; Woychik et al., 1985; Woychik et al., 1990). The limb deformity is marked by synostoses and syndactyly of all 4 limbs. The renal defect consists of unilateral or bilateral renal aplasia.
The relationship between gremlin (GREM1; 603054) and Fmn1 is interesting because of their proximity in the mouse genome. The Fmn1 transcript comprises a large number of exons with the most 3-prime exon located approximately 40 kb from the Grem1 open reading frame. Given the apparently identical phenotype of ld mice to gremlin mutant mice and the proximity of Fmn1 to Grem1, Khokha et al. (2003) tested whether gremlin would complement ld. They found that gremlin fails to complement ld and thus identified another ld allele. Although a complex interaction between Fmn1 and gremlin is possible, Khokha et al. (2003) favored the idea that the ld mutations affect gremlin expression directly and that they lie in cis-regulatory elements for gremlin expression.
Zhou et al. (2009) generated Fmn1 pro/pro mice, which fail to produce detectable Fmn1 proteins or any of the full-length Fmn1 splice variants. They found that Fmn1 pro/pro exhibited only 4 digits per limb, a deformed posterior metatarsal, phalangeal soft tissue fusion, and absence of the fibula, with 100% penetrance on the FVB background and 66% penetrance on the 129/SvEv background. The Fmn1-mutant allele did not genetically disrupt the characterized gremlin enhancer; indeed, gremlin RNA expression was upregulated at the 35 somite stage of development. The Fmn1 pro/pro mice demonstrated increased bone morphogenetic protein (Bmp) activity, as evidenced by upregulation of Msx1 (142983) and a decrease in Fgf4 (164980) within the apical ectodermal ridge. Enhanced activity downstream of the Bmp receptor in cells where Fmn1 was perturbed suggested a role for Fmn1 in repression of Bmp signaling.
Hu et al. (2014) found that knockout (KO) of both Flnb and Fmn1 in mice resulted in a more severe reduction in body size, weight, and growth plate length than that observed in mice with KO of either gene alone. In Flnb/Fmn1 double-KO mice, shortening of long bones was associated with decreased chondrocyte proliferation and an overall delay in ossification. Comparison of Fmn1 KO mice with Flnb/Fmn1 double-KO mice revealed nonoverlapping functions for Fmn1 and Flnb in the prehypertrophic zone, with loss of Fmn1 resulting in a decrease in the width of the prehypertrophic zone, and loss of Flnb causing premature differentiation of the prehypertrophic zone.
Green, M. C. Catalog of mutant genes and polymorphic loci. In: Genetic Variants and Strains of the Laboratory Mouse. New York: Gustav Fischer Verlag (pub.) 1981. P. 137.
Hu, J., Lu, J., Lian, G., Ferland, R. J., Dettenhofer, M., Sheen, V. L. Formin 1 and filamin B physically interact to coordinate chondrocyte proliferation and differentiation in the growth plate. Hum. Molec. Genet. 23: 4663-4673, 2014. [PubMed: 24760772] [Full Text: https://doi.org/10.1093/hmg/ddu186]
Khokha, M. K., Hsu, D., Brunet, L. J., Dionne, M. S., Harland, R. M. Gremlin is the BMP antagonist required for maintenance of Shh and Fgf signals during limb patterning. Nature Genet. 34: 303-307, 2003. [PubMed: 12808456] [Full Text: https://doi.org/10.1038/ng1178]
Kobielak, A., Pasolli, H. A., Fuchs, E. Mammalian formin-1 participates in adherens junctions and polymerization of linear actin cables. Nature Cell Biol. 6: 21-30, 2004. [PubMed: 14647292] [Full Text: https://doi.org/10.1038/ncb1075]
Maas, R. L., Jepeal, L. I., Elfering, S. L., Holcombe, R. F., Morton, C. C., Eddy, R. L., Byers, M. G., Shows, T. B., Leder, P. A human gene homologous to the formin gene residing at the murine limb deformity locus: chromosomal location and RFLPs. Am. J. Hum. Genet. 48: 687-695, 1991. [PubMed: 1673046]
Richard, I., Broux, O., Chiannilkulchai, N., Fougerousse, F., Allamand, V., Bourg, N., Brenguier, L., Devaud, C., Pasturaud, P., Roudaut, C., Lorenzo, F., Sebastiani-Kabatchis, C., Schultz, R. A., Polymeropoulos, M. H., Gyapay, G., Auffray, C., Beckmann, J. S. Regional localization of human chromosome 15 loci. Genomics 23: 619-627, 1994. [PubMed: 7851890] [Full Text: https://doi.org/10.1006/geno.1994.1550]
Richard, I., Broux, O., Hillaire, D., Cherif, D., Fougerousse, F., Cohen, D., Beckmann, J. S. Mapping of the formin gene and exclusion as a candidate gene for the autosomal recessive form of limb-girdle muscular dystrophy. Hum. Molec. Genet. 1: 621-624, 1992. [PubMed: 1363783] [Full Text: https://doi.org/10.1093/hmg/1.8.621]
Vogt, T. F., Jackson-Grusby, L., Rush, J., Leder, P. Formins: phosphoprotein isoforms encoded by the mouse limb deformity locus. Proc. Nat. Acad. Sci. 90: 5554-5558, 1993. [PubMed: 8516300] [Full Text: https://doi.org/10.1073/pnas.90.12.5554]
Wang, C. C., Chan, D. C., Leder, P. The mouse formin (Fmn) gene: genomic structure, novel exons, and genetic mapping. Genomics 39: 303-311, 1997. [PubMed: 9119367] [Full Text: https://doi.org/10.1006/geno.1996.4519]
Woychik, R. P., Generoso, W. M., Russell, L. B., Cain, K. T., Cacheiro, N. L. A., Bultman, S. J., Selby, P. B., Dickinson, M. E., Hogan, B. L. M., Rutledge, J. C. Molecular and genetic characterization of a radiation-induced structural rearrangement in mouse chromosome 2 causing mutations at the limb deformity and agouti loci. Proc. Nat. Acad. Sci. 87: 2588-2592, 1990. [PubMed: 2320577] [Full Text: https://doi.org/10.1073/pnas.87.7.2588]
Woychik, R. P., Maas, R. L., Zeller, R., Vogt, T. F., Leder, P. 'Formins:' proteins deduced from the alternative transcripts of the limb-deformity gene. Nature 346: 850-853, 1990. [PubMed: 2392150] [Full Text: https://doi.org/10.1038/346850a0]
Woychik, R. P., Stewart, T. A., Davis, L. G., D'Eustachio, P., Leder, P. An inherited limb deformity created by insertional mutagenesis in a transgenic mouse. Nature 318: 36-40, 1985. [PubMed: 2997621] [Full Text: https://doi.org/10.1038/318036a0]
Zhou, F., Leder, P., Zuniga, A., Dettenhofer, M. Formin1 disruption confers oligodactylism and alters Bmp signaling. Hum. Molec. Genet. 18: 2472-2482, 2009. [PubMed: 19383632] [Full Text: https://doi.org/10.1093/hmg/ddp185]
Zuniga, A., Haramis, A.-P. G., McMahon, A. P., Zeller, R. Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds. Nature 401: 598-602, 1999. [PubMed: 10524628] [Full Text: https://doi.org/10.1038/44157]