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Development. 2018 Mar 22;145(6). pii: dev159830. doi: 10.1242/dev.159830.

Regulatory integration of Hox factor activity with T-box factors in limb development.

Author information

1
Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal, Montréal, QC, H2W 1R7 Canada.
2
Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6 Canada.
3
Department of Experimental Medicine, McGill University, Montreal, QC, H4A 3J1 Canada.
4
Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal, Montréal, QC, H2W 1R7 Canada Jacques.Drouin@ircm.qc.ca.
5
Departement de Biochimie, Faculté de Médecine, Université de Montréal, Montréal, QC, H3J 3J7 Canada.

Abstract

In tetrapods, Tbx4, Tbx5 and Hox cluster genes are crucial for forelimb and hindlimb development and mutations in these genes are responsible for congenital limb defects. The molecular basis of their integrated mechanisms of action in the context of limb development remains poorly understood. We studied Tbx4 and Hoxc10 owing to their overlapping loss-of-function phenotypes and colocalized expression in mouse hindlimb buds. We report an extensive overlap between Tbx4 and Hoxc10 genome occupancy and their putative target genes. Tbx4 and Hoxc10 interact directly with each other, have the ability to bind to a previously unrecognized T-box-Hox composite DNA motif and show synergistic activity when acting on reporter genes. Pitx1, the master regulator for hindlimb specification, also shows extensive genomic colocalization with Tbx4 and Hoxc10. Genome occupancy by Tbx4 in hindlimb buds is similar to Tbx5 occupancy in forelimbs. By contrast, another Hox factor, Hoxd13, also interacts with Tbx4/Tbx5 but antagonizes Tbx4/Tbx5-dependent transcriptional activity. Collectively, the modulation of Tbx-dependent activity by Hox factors acting on common DNA targets may integrate different developmental processes for the balanced formation of proportionate limbs.

KEYWORDS:

ChIPseq; Hoxa13; Hoxc10; Hoxd13; Limb specification; Pitx1; Regulatory network; Tbx4; Tbx5

PMID:
29490982
DOI:
10.1242/dev.159830
[Indexed for MEDLINE]
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