We dissect genetically a gene regulatory network, including the transcription factors Tbx4, Pitx1 and Isl1 that act cooperatively to establish the hindlimb bud and identify key differences in the pathways that initiate formation of the hindlimb and forelimb. Using live image analysis of limb mesenchyme cells undergoing chondrogenesis in micromass culture, we distinguish a series of changes in cellular behaviours and cohesiveness that are required for chondrogenic precursors to undergo differentiation. Furthermore, we provide evidence that the proximal hindlimb defects in the Tbx4 mutant result from a failure in the early differentiation step of chondroprogenitors into chondrocytes, providing a novel explanation for the origins of proximally-biased limb defects.
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RESEARCH ARTICLE|
23 August 2021
Tbx4 function during hindlimb development reveals a novel mechanism to explain the origins of proximal limb defects
Veronique Duboc,
1
Randall Centre for Cell and Molecular Biophysics, King's College London, Guy's Campus, London SE1 1UL
, UK
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Fatima Sulaiman,
Fatima Sulaiman
1
Randall Centre for Cell and Molecular Biophysics, King's College London, Guy's Campus, London SE1 1UL
, UK
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Eleanor Feneck,
Eleanor Feneck
1
Randall Centre for Cell and Molecular Biophysics, King's College London, Guy's Campus, London SE1 1UL
, UK
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Anna Kucharska,
Anna Kucharska
‡
1
Randall Centre for Cell and Molecular Biophysics, King's College London, Guy's Campus, London SE1 1UL
, UK
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Donald Bell,
Donald Bell
2
Light Microscopy, Francis Crick Institute, 1 Midland Road, London, NW1 1AT
, UK
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Muriel Holder-Espinasse,
Muriel Holder-Espinasse
3
Clinical Genetics Department, Guy's Hospital, London SE1 9RT
, UK
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Malcolm P.O. Logan
Malcolm P.O. Logan
§
1
Randall Centre for Cell and Molecular Biophysics, King's College London, Guy's Campus, London SE1 1UL
, UK
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1
Randall Centre for Cell and Molecular Biophysics, King's College London, Guy's Campus, London SE1 1UL
, UK
Fatima Sulaiman
1
Randall Centre for Cell and Molecular Biophysics, King's College London, Guy's Campus, London SE1 1UL
, UK
Eleanor Feneck
1
Randall Centre for Cell and Molecular Biophysics, King's College London, Guy's Campus, London SE1 1UL
, UK
Anna Kucharska
‡
1
Randall Centre for Cell and Molecular Biophysics, King's College London, Guy's Campus, London SE1 1UL
, UK
Donald Bell
2
Light Microscopy, Francis Crick Institute, 1 Midland Road, London, NW1 1AT
, UK
Muriel Holder-Espinasse
3
Clinical Genetics Department, Guy's Hospital, London SE1 9RT
, UK
Malcolm P.O. Logan
§
1
Randall Centre for Cell and Molecular Biophysics, King's College London, Guy's Campus, London SE1 1UL
, UK
*
Present addresses: Université Côte d'Azur, CHU de Nice, Inserm, CNRS, IRCAN, Nice, France
‡
Present addresses: Stem Cell Biology and Developmental Genetics, Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
Received:
02 Mar 2021
Accepted:
02 Aug 2021
Online ISSN: 1477-9129
Print ISSN: 0950-1991
Funding Group:
- Award Group:
- Funder(s): Medical Research Council
- Award Id(s): MC PC 13052
- Funder(s):
© 2021. Published by The Company of Biologists Ltd
2021
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Development dev.199580.
Article history
Received:
02 Mar 2021
Accepted:
02 Aug 2021
Currently Viewing Accepted Manuscript - Newer Version Available
24 Sep 2021
Citation
Veronique Duboc, Fatima Sulaiman, Eleanor Feneck, Anna Kucharska, Donald Bell, Muriel Holder-Espinasse, Malcolm P.O. Logan; Tbx4 function during hindlimb development reveals a novel mechanism to explain the origins of proximal limb defects. Development 2021; dev.199580. doi: https://doi.org/10.1242/dev.199580
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