FOXP2: novel exons, splice variants, and CAG repeat length stability

Bruce, Heather; Margolis, Russell L.

doi:10.1007/s00439-002-0768-5

Cited by 73 publications

(79 citation statements)

References 37 publications

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“…Pure CAG repeats are less stable than repeats encoded by a mix of interspersed CAG and CAA triplets (Gao et al , 2008 ). An example of the latter is FoxP2, a transcription factor needed for speech and language development in humans, with a long, quite stable polyQ stretch of 40 glutamines (Bruce and Margolis , 2002 ;Enard et al , 2002 ;Webb and Zhang , 2005 ). Most likely, CAA interruptions counteract CAG repeat slippage and expansions in DNA.…”

Section: Discussionmentioning

confidence: 99%

Polyglutamine tracts as modulators of transcriptional activation from yeast to mammals

Atanesyan¹,

Günther

Dichtl

et al. 2012

Biological Chemistry

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Microsatellite repeats are genetically unstable and subject to expansion and shrinkage. A subset of them, triplet repeats, can occur within the coding region and specify homomeric tracts of amino acids. Polyglutamine (polyQ) tracts are enriched in eukaryotic regulatory proteins, notably transcription factors, and we had shown before that they can contribute to transcriptional activation in mammalian cells. Here we generalize this fi nding by also including evolutionarily divergent organisms, namely, Drosophila and baker ' s yeast. In all three systems, Gal4-based model transcription factors were more active if they harbored a polyQ tract, and the activity depended on the length of the tract. By contrast, a polyserine tract was inactive. PolyQs acted from either an internal or a C-terminal position, thus ruling out a merely structural ' linker ' effect. Finally, a two-hybrid assay in mammalian cells showed that polyQ tracts can interact with each other, supporting the concept that a polyQ-containing transcription factor can recruit other factors with polyQ tracts or glutamine-rich activation domains. The widespread occurrence of polyQ repeats in regu latory proteins suggests a benefi cial role; in addition to the contribution to transcriptional activity, their genetic instability might help a species to adapt to changing environmental conditions in a potentially reversible manner.

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Section: Discussionmentioning

confidence: 99%

Polyglutamine tracts as modulators of transcriptional activation from yeast to mammals

Atanesyan¹,

Günther

Dichtl

et al. 2012

Biological Chemistry

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“…Foxp2 contains many multifunctional domains and exhibits various alternative splicing products (16). Unlike the affected KE members expressing the FOXP2 (R553H) mutant, Foxp2-KO mice may be completely deficient for all of the functions of Foxp2 and its alternative splicing products (16,20). Which functional domain of Foxp2 or alternative splicing product of Foxp2 functions in the molecular mechanism of mouse USVs and whether the phenotype of Foxp2-KO mice is due to the loss of function of forkhead domain were not previously established.…”

Section: Discussion Common Molecular Mechanism Shared With Mouse Usvsmentioning

confidence: 99%

Ultrasonic vocalization impairment of Foxp2 (R552H) knockin mice related to speech-language disorder and abnormality of Purkinje cells

Fujita

Tanabe²,

Shiota³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

200

205

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Previous studies have demonstrated that mutation in the forkhead domain of the forkhead box P2 (FOXP2) protein (R553H) causes speech-language disorders. To further analyze FOXP2 function in speech learning, we generated a knockin (KI) mouse for Foxp2 (R552H) [Foxp2 (R552H)-KI], corresponding to the human FOXP2 (R553H) mutation, by homologous recombination. Homozygous Foxp2 (R552H)-KI mice showed reduced weight, immature development of the cerebellum with incompletely folded folia, Purkinje cells with poor dendritic arbors and less synaptophysin immunoreactivity, and achieved crisis stage for survival 3 weeks after birth. At postnatal day 10, these mice also showed severe ultrasonic vocalization (USV) and motor impairment, whereas the heterozygous Foxp2 (R552H)-KI mice exhibited modest impairments. Similar to the wild-type protein, Foxp2 (R552H) localized in the nuclei of the Purkinje cells and the thalamus, striatum, cortex, and hippocampus (CA1) neurons of the homozygous Foxp2 (R552H)-KI mice (postnatal day 10), and some of the neurons showed nuclear aggregates of Foxp2 (R552H). In addition to the immature development of the cerebellum, Foxp2 (R552H) nuclear aggregates may further compromise the function of the Purkinje cells and cerebral neurons of the homozygous mice, resulting in their death. In contrast, heterozygous Foxp2 (R552H)-KI mice, which showed modest impairment of USVs with different USV qualities and which did not exhibit nuclear aggregates, should provide insights into the common molecular mechanisms between the mouse USV and human speech learning and the relationship between the USV and motor neural systems.KE family ͉ nuclear aggregation ͉ autism ͉ endoplasmic reticulum stress T he phenotype of the speech-language disorder segregates as an autosomal dominant trait. The KE family consists of three generations in which approximately half of the members (15 members) have severe articulation difficulties accompanied by verbal and orofacial impairments. The speech difficulties cannot be fully attributed to the basic impairment of orofacial praxis; the affected KE members normally perform single simple oral movements but have trouble with language comprehension, including grammar as well as production (1-5). Recent studies in the KE family identified the forkhead box P2 (FOXP2) gene as the responsible genetic factor and found that a missense mutation (R553H) in the forkhead domain of FOXP2 cosegregates with the disorder in this family (2-5).In addition to a forkhead domain with a winged-helix DNA binding domain (6), FOXP2 also contains a glutamine-rich region (polyQ tract), zinc finger, and a leucine zipper motif for homodimerization and heterodimerization with Foxp1, 2, and 4 family members (7). FOXP2 also interacts with the C-terminal binding protein (CtBP) to act as a transcriptional repressor (7). The familial FOXP2 mutated protein (R553H) exhibits reduced DNA binding and defects in nuclear localization in vitro (8, 9). In addition, a nonsense mutation (R328X), another mutation related to the spe...

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“…Indeed, Western blotting using the JC12 antibody identified up to three different molecular weight proteins in MCF-7 breast cancer cells that may be the products of such splice variants. There are numerous examples of proteins with differing biological activities generated from a single gene by alternative splicing and extensive alternative splicing has also been reported for the FOXP2 gene (18). Moreover, the expression of alternatively spliced FOXP1 proteins may explain the presence of cytoplasmic staining that was observed in some tumors that was not identified in normal breast tissues.…”

Section: Discussionmentioning

confidence: 99%

Expression of the Forkhead Transcription Factor FOXP1 Is Associated with Estrogen Receptor α and Improved Survival in Primary Human Breast Carcinomas

Fox

Brown

Han

et al. 2004

Clinical Cancer Research

102

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Purpose: The FOXP1 protein belongs to a functionally diverse family of winged-helix or forkhead transcription factors that have diverse roles in cellular proliferation, differentiation, and neoplastic transformation. The FOXP1 gene, which maps to 3p14, shows common loss of heterozygosity in breast tumors and is a candidate tumor suppressor gene. However, its role in breast cancer is unknown.Experimental Design: We have therefore investigated the pattern of FOXP1 expression in whole sections from normal (n ‫؍‬ 16) and neoplastic (n ‫؍‬ 90) breast tissues and correlated the level of expression in 283 invasive breast carcinomas on tissue microarrays with clinicopathological factors and survival. Because a relationship with estrogen receptor (ER) was identified, estrogen (17␤-estradiol) regulation and ER/FOXP1 colocalization was also investigated.Results: Expression of FOXP1 was significantly positively associated with ER (P ‫؍‬ 0.03) and negatively with epidermal growth factor receptor (P ‫؍‬ 0.01) but no association with age (P ‫؍‬ 0.91), lymph node status (P ‫؍‬ 0.94), size (P ‫؍‬ 0.76), or grade (P ‫؍‬ 0.22). In a multivariate analysis of survival, FOXP1 expression was associated with a significantly improved relapse-free (P ‫؍‬ 0.03) and borderline overall (P ‫؍‬ 0.09) survival. Unlike normal breast, there was common coexpression of FOXP1 and ER in cell lines and tumors, but no 17␤-estradiol (10 -9 M) regulation of FOXP1 in MCF-7 cells was demonstrated.Conclusions: Our findings support a role for FOXP1 as a potential ER coregulator in human breast carcinoma and suggest that it may also independently regulate additional important pathways that control the progression of breast cancer.

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FOXP2: novel exons, splice variants, and CAG repeat length stability

Cited by 73 publications

References 37 publications

Polyglutamine tracts as modulators of transcriptional activation from yeast to mammals

Polyglutamine tracts as modulators of transcriptional activation from yeast to mammals

Ultrasonic vocalization impairment of Foxp2 (R552H) knockin mice related to speech-language disorder and abnormality of Purkinje cells

Expression of the Forkhead Transcription Factor FOXP1 Is Associated with Estrogen Receptor α and Improved Survival in Primary Human Breast Carcinomas

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