Hoxb6 can interfere with somitogenesis in the posterior embryo through a mechanism independent of its rib-promoting activity

Abstract

Formation of the vertebrate axial skeleton requires coordinated Hox gene activity. Hox group 6 genes are involved in the formation of the thoracic area owing to their unique rib-promoting properties. Here we show that the linker region (LR) connecting the homeodomain and the hexapeptide is essential for Hoxb6 rib-promoting activity in mice. The LR-defective Hoxb6 protein was still able to bind a target enhancer together with Pax3, producing a dominant-negative effect, indicating that the LR brings additional regulatory factors to target DNA elements. We also found an unexpected association between Hoxb6 and segmentation in the paraxial mesoderm. In particular, Hoxb6 can disturb somitogenesis and anterior-posterior somite patterning by dysregulation of Lfng expression. Interestingly, this interaction occurred differently in thoracic versus more caudal embryonic areas, indicating functional differences in somitogenesis before and after the trunk-to-tail transition. Our results suggest the requirement of precisely regulated Hoxb6 expression for proper segmentation at tailbud stages.

Tail Bud Progenitor Activity Relies on a Network Comprising Gdf11, Lin28, and Hox13 Genes

“…Paraxial mesoderm formation and somitogenesis also have distinct mechanistic requirements whether they derive from epiblast-or tail bud-residing NMPs. Indeed, it has been observed a differential requirement for the cycling behavior of Lfng expression (Shifley et al, 2008;Williams et al, 2014), as well as distinctive sensitivities to the presence of Hoxb6 activity (Casaca et al, 2016) at trunk or tail axial levels.…”

Deconstructing the molecular mechanisms shaping the vertebrate body plan

“…Tail somites were also shown to be more resilient to reductions in Lfng dosage than their trunk counterparts [43]. Conversely, Hoxb6 readily interferes with somite formation at tail levels but have no negative effects on the same process in more anterior regions, further supporting mechanistic differences in somitogenesis during primary and secondary body formation [44].…”

The vertebrate tail: a gene playground for evolution

“…In particular, blocking Lfng cycling activity or reducing its expression levels interfere with trunk but not tail somite formation [56,57]. Conversely, forced expression of Hoxb6 in the presomitic mesoderm blocks tail bud but not trunk somitogenesis [58]. Thus, an ever-growing body of functional and molecular data indicates that, despite the morphological continuity of the anterior-posterior axis supported by common regulatory proteins (e.g.…”