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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Patterning / genetics*
  • Electrophoretic Mobility Shift Assay
  • Gene Expression Regulation, Developmental
  • Genes, Homeobox / genetics*
  • Hindlimb / metabolism
  • Immunoprecipitation
  • Limb Buds / metabolism*
  • Mice
  • Morphogenesis / genetics
  • Paired Box Transcription Factors / metabolism
  • T-Box Domain Proteins / metabolism*

Substances

  • Paired Box Transcription Factors
  • T-Box Domain Proteins
  • homeobox protein PITX1