Nr6a1 controls axially-restricted body elongation, segmentation, patterning and lineage allocation

Abstract

The vertebrate main-body axis is laid down during embryonic stages in an anterior-to-posterior (head-to-tail) direction, driven and supplied by posteriorly located progenitors. For the vertebral column, the process of axial progenitor cell expansion that drives elongation, and the process of segmentation which allocates progenitor-descendants into repeating pre-vertebral units, occurs seemingly uninterrupted from the first to the last vertebra. Nonetheless, there is clear developmental and evolutionary support for two discrete modules controlling processes within different axial regions: a trunk and a tail module. Here, we identify Nuclear receptor subfamily 6 group A member 1 (Nr6a1) as a master regulator of elongation, segmentation, patterning and lineage allocation specifically within the trunk region of the mouse. Both gain- and loss-of-function in vivo analyses revealed that the precise level of Nr6a1 acts as a rheostat, expanding or contracting vertebral number of the trunk region autonomously from other axial regions. Moreover, Nr6a1 was found to be required for segmentation, but only for trunk-forming somites, with the timely clearance of Nr6a1 critical in supporting tail formation. In parallel with these morphological outcomes, we reveal Nr6a1 as a novel regulator of global Hox signatures within axial progenitors, preventing the precocious expression of multiple posterior Hox genes as the trunk is being laid down and thus reinforcing that patterning and elongation are coordinated. Finally, our data supports a crucial role for Nr6a1 in regulating gene regulatory networks that guide cell lineage choice of axial progenitors between neural and mesodermal fate. Collectively, these data reveal an axially-restricted role for Nr6a1 in all major cellular and tissue-level events required for vertebral column formation, supporting the view that modulation of Nr6a1 expression level or function is likely to underpin evolutionary changes in axial formulae that exclusively alter the trunk region.