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Development. 2017 Sep 15;144(18):3325-3335. doi: 10.1242/dev.154864. Epub 2017 Aug 14.

Pitx1 directly modulates the core limb development program to implement hindlimb identity.

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Institut de Recherches Cliniques de Montréal, Montréal, QC, H2W 1R7 Canada.
Department of Experimental Medicine, McGill University, Montreal, QC, H4A 3J1 Canada.
Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6 Canada.
Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, QC, H3A 0G1 Canada.
Institut de Recherches Cliniques de Montréal, Montréal, QC, H2W 1R7 Canada


Forelimbs (FLs) and hindlimbs (HLs) develop complex musculoskeletal structures that rely on the deployment of a conserved developmental program. Pitx1, a transcription factor gene with expression restricted to HL and absent from FL, plays an important role in generating HL features. The genomic mechanisms by which Pitx1 effects HL identity remain poorly understood. Here, we use expression profiling and analysis of direct Pitx1 targets to characterize the HL- and FL-restricted genetic programs in mouse and situate the Pitx1-dependent gene network within the context of limb-specific gene regulation. We show that Pitx1 is a crucial component of a narrow network of HL-restricted regulators, acting on a developmental program that is shared between FL and HL. Pitx1 targets sites that are in a similar chromatin state in FL and HL and controls expression of patterning genes as well as the chondrogenic program, consistent with impaired chondrogenesis in Pitx1-/- HL. These findings support a model in which multifactorial actions of a limited number of HL regulators redirect the generic limb development program in order to generate the unique structural features of the limb.


ChIPseq; Expression profiling; Limb specification; Mouse; Regulatory network; Tbx5

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