Genetic basis of hindlimb loss in a naturally occurring vertebrate model

Emily K. Don, Tanya A. De Jong-Curtain, Karen Doggett, Thomas E. Hall, Benjamin Heng, Andrew P. Badrock, Claire Winnick, Garth A. Nicholson, Gilles J. Guillemin, Peter D. Currie, Daniel Hesselson, Joan K. Heath, Nicholas J. Cole

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Here we genetically characterise pelvic finless, a naturally occurring model of hindlimb loss in zebrafish that lacks pelvic fin structures, which are homologous to tetrapod hindlimbs, but displays no other abnormalities. Using a hybrid positional cloning and next generation sequencing approach, we identified mutations in the nuclear localisation signal (NLS) of T-box transcription factor 4 (Tbx4) that impair nuclear localisation of the protein, resulting in altered gene expression patterns during pelvic fin development and the failure of pelvic fin development. Using a TALEN-induced tbx4 knockout allele we confirm that mutations within the Tbx4 NLS (A78V; G79A) are sufficient to disrupt pelvic fin development. By combining histological, genetic, and cellular approaches we show that the hindlimb initiation gene tbx4 has an evolutionarily conserved, essential role in pelvic fin development. In addition, our novel viable model of hindlimb deficiency is likely to facilitate the elucidation of the detailed molecular mechanisms through which Tbx4 functions during pelvic fin and hindlimb development.

LanguageEnglish
Pages359-366
Number of pages8
JournalBiology Open
Volume5
Issue number3
DOIs
Publication statusPublished - 15 Mar 2016

Fingerprint

Hindlimb
fins
Vertebrates
vertebrates
Cloning
Nuclear Localization Signals
Gene expression
nuclear localization signals
Transcription Factors
Genes
Mutation
mutation
Zebrafish
Nuclear Proteins
Proteins
Organism Cloning
Danio rerio
Alleles
hindlimbs
molecular cloning

Bibliographical note

Copyright the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Cite this

Don, Emily K. ; De Jong-Curtain, Tanya A. ; Doggett, Karen ; Hall, Thomas E. ; Heng, Benjamin ; Badrock, Andrew P. ; Winnick, Claire ; Nicholson, Garth A. ; Guillemin, Gilles J. ; Currie, Peter D. ; Hesselson, Daniel ; Heath, Joan K. ; Cole, Nicholas J. / Genetic basis of hindlimb loss in a naturally occurring vertebrate model. In: Biology Open. 2016 ; Vol. 5, No. 3. pp. 359-366.
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abstract = "Here we genetically characterise pelvic finless, a naturally occurring model of hindlimb loss in zebrafish that lacks pelvic fin structures, which are homologous to tetrapod hindlimbs, but displays no other abnormalities. Using a hybrid positional cloning and next generation sequencing approach, we identified mutations in the nuclear localisation signal (NLS) of T-box transcription factor 4 (Tbx4) that impair nuclear localisation of the protein, resulting in altered gene expression patterns during pelvic fin development and the failure of pelvic fin development. Using a TALEN-induced tbx4 knockout allele we confirm that mutations within the Tbx4 NLS (A78V; G79A) are sufficient to disrupt pelvic fin development. By combining histological, genetic, and cellular approaches we show that the hindlimb initiation gene tbx4 has an evolutionarily conserved, essential role in pelvic fin development. In addition, our novel viable model of hindlimb deficiency is likely to facilitate the elucidation of the detailed molecular mechanisms through which Tbx4 functions during pelvic fin and hindlimb development.",
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Don, EK, De Jong-Curtain, TA, Doggett, K, Hall, TE, Heng, B, Badrock, AP, Winnick, C, Nicholson, GA, Guillemin, GJ, Currie, PD, Hesselson, D, Heath, JK & Cole, NJ 2016, 'Genetic basis of hindlimb loss in a naturally occurring vertebrate model' Biology Open, vol. 5, no. 3, pp. 359-366. https://doi.org/10.1242/bio.016295

Genetic basis of hindlimb loss in a naturally occurring vertebrate model. / Don, Emily K.; De Jong-Curtain, Tanya A.; Doggett, Karen; Hall, Thomas E.; Heng, Benjamin; Badrock, Andrew P.; Winnick, Claire; Nicholson, Garth A.; Guillemin, Gilles J.; Currie, Peter D.; Hesselson, Daniel; Heath, Joan K.; Cole, Nicholas J.

In: Biology Open, Vol. 5, No. 3, 15.03.2016, p. 359-366.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Genetic basis of hindlimb loss in a naturally occurring vertebrate model

AU - Don,Emily K.

AU - De Jong-Curtain,Tanya A.

AU - Doggett,Karen

AU - Hall,Thomas E.

AU - Heng,Benjamin

AU - Badrock,Andrew P.

AU - Winnick,Claire

AU - Nicholson,Garth A.

AU - Guillemin,Gilles J.

AU - Currie,Peter D.

AU - Hesselson,Daniel

AU - Heath,Joan K.

AU - Cole,Nicholas J.

N1 - Copyright the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2016/3/15

Y1 - 2016/3/15

N2 - Here we genetically characterise pelvic finless, a naturally occurring model of hindlimb loss in zebrafish that lacks pelvic fin structures, which are homologous to tetrapod hindlimbs, but displays no other abnormalities. Using a hybrid positional cloning and next generation sequencing approach, we identified mutations in the nuclear localisation signal (NLS) of T-box transcription factor 4 (Tbx4) that impair nuclear localisation of the protein, resulting in altered gene expression patterns during pelvic fin development and the failure of pelvic fin development. Using a TALEN-induced tbx4 knockout allele we confirm that mutations within the Tbx4 NLS (A78V; G79A) are sufficient to disrupt pelvic fin development. By combining histological, genetic, and cellular approaches we show that the hindlimb initiation gene tbx4 has an evolutionarily conserved, essential role in pelvic fin development. In addition, our novel viable model of hindlimb deficiency is likely to facilitate the elucidation of the detailed molecular mechanisms through which Tbx4 functions during pelvic fin and hindlimb development.

AB - Here we genetically characterise pelvic finless, a naturally occurring model of hindlimb loss in zebrafish that lacks pelvic fin structures, which are homologous to tetrapod hindlimbs, but displays no other abnormalities. Using a hybrid positional cloning and next generation sequencing approach, we identified mutations in the nuclear localisation signal (NLS) of T-box transcription factor 4 (Tbx4) that impair nuclear localisation of the protein, resulting in altered gene expression patterns during pelvic fin development and the failure of pelvic fin development. Using a TALEN-induced tbx4 knockout allele we confirm that mutations within the Tbx4 NLS (A78V; G79A) are sufficient to disrupt pelvic fin development. By combining histological, genetic, and cellular approaches we show that the hindlimb initiation gene tbx4 has an evolutionarily conserved, essential role in pelvic fin development. In addition, our novel viable model of hindlimb deficiency is likely to facilitate the elucidation of the detailed molecular mechanisms through which Tbx4 functions during pelvic fin and hindlimb development.

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JO - Biology Open

T2 - Biology Open

JF - Biology Open

SN - 2046-6390

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Don EK, De Jong-Curtain TA, Doggett K, Hall TE, Heng B, Badrock AP et al. Genetic basis of hindlimb loss in a naturally occurring vertebrate model. Biology Open. 2016 Mar 15;5(3):359-366. https://doi.org/10.1242/bio.016295