HOX AND SHOX GENES IN LIMB DEVELOPMENT Prof. Denis Duboule, Geneva, Switzerland    - Biography English - 2007-10-06

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Background and aims: The development of our limbs is critically dependent upon a set of homeobox containing genes; the Hox genes. These genes encode transcription factors involved in progressively organizing and growing the various limb skeletal elements. For the past 15 years,we have used a genetic approach, in mice, to try and understand both the regulation and function of this gene family, as well as their potential impact in various human and rodent genetic syndromes. Amongst the potential target genes regulated by the Hox gene family, we discovered the mouse Shox2 gene as being possibly repressed by Hox genes in the distal part of the developing limb. As their Hox relatives, Shox2 contains a homeobox and also encodes for a transcription factor.

Methods: We used mouse molecular genetics and transgenesis.

Results: Deficiencies or mutations in the human X-linked pseudoautosomal SHOX gene are associated with a series of short stature conditions, including Turner syndrome, Leri-Weill dyschondrosteosis and Langer mesomelic dysplasia. While this gene is absent from the mouse genome, Shox2 seems to be the most closely related paralogous gene, as it displays a similar expression pattern in developing limbs. Here, we report that the conditional inactivation of Shox2 in developing appendages leads to a strong phenotype, similar to the human conditions, though affecting a different proximo-distal limb segment. Furthermore, we establish the cellular aetiology of these defects and show that Shox2 acts upstream the Runx2 gene, a key regulator of chondrogenesis.

Conclusions: Both Shox2 and Hox genes are critical for proper development of mammalian limbs.