Newt Hoxa13 has an essential and predominant role in digit formation during development and regeneration.

The 5'Hox genes play crucial roles in limb development and specify regions in the proximal-distal axis of limbs. However, there is no direct genetic evidence that Hox genes are essential for limb development in non-mammalian tetrapods or for limb regeneration. Here, we produced single to quadruple Hox13 paralog mutants using the CRISPR/Cas9 system in newts (Pleurodeles waltl), which have strong regenerative capacities, and also produced germline mutants. We show that Hox13 genes are essential for digit formation in development, as in mice. In addition, Hoxa13 has a predominant role in digit formation, unlike in mice. The predominance is probably due to the restricted expression pattern of Hoxd13 in limb buds and the strong dependence of Hoxd13 expression on Hoxa13. Finally, we demonstrate that Hox13 genes are also necessary for digit formation in limb regeneration. Our findings reveal that the general function of Hox13 genes is conserved between limb development and regeneration, and across taxa. The predominance of Hoxa13 function both in newt limbs and fish fins, but not in mouse limbs, suggests a potential contribution of Hoxa13 function in fin-to-limb transition.

Paralogous HOX13 Genes in Human Cancers.

Hox genes (HOX in humans), an evolutionary preserved gene family, are key determinants of embryonic development and cell memory gene program. Hox genes are organized in four clusters on four chromosomal loci aligned in 13 paralogous groups based on sequence homology (Hox gene network). During development Hox genes are transcribed, according to the rule of "spatio-temporal collinearity", with early regulators of anterior body regions located at the 3' end of each Hox cluster and the later regulators of posterior body regions placed at the distal 5' end. The onset of 3' Hox gene activation is determined by Wingless-type MMTV integration site family (Wnt) signaling, whereas 5' Hox activation is due to paralogous group 13 genes, which act as posterior-inhibitors of more anterior Hox proteins (posterior prevalence). Deregulation of HOX genes is associated with developmental abnormalities and different human diseases. Paralogous HOX13 genes (HOX A13, HOX B13, HOX C13 and HOX D13) also play a relevant role in tumor development and progression. In this review, we will discuss the role of paralogous HOX13 genes regarding their regulatory mechanisms during carcinogenesis and tumor progression and their use as biomarkers for cancer diagnosis and treatment.