Nr6a1 controls axially-restricted body elongation, patterning and lineage allocation [dataset 1]

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 axis elongation, and the process of segmentation which allocates these progenitors into repeating 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 module and a tail module. The secreted signal Gdf11 has been identified as a principal regulator of timing the trunk-to-tail (T-to-T) transition, but has pleiotropic effects across much of the main body axis, highlighting the need to reveal intrinsic regulatory networks that function to exclusively control one or the other module. Here, we identify Nuclear receptor subfamily 6 group A member 1 (Nr6a1) as a master regulator of elongation, patterning and lineage allocation specifically within the trunk region of the mouse. Both gain- and loss-of-function in vivo analysis 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, the timely clearance of Nr6a1 observed at the T-to-T transition was essential in allowing the tail module to operate correctly. In parallel with these effects on vertebral number, we show that Nr6a1 controls the timely progression 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, our data reveals 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 may underpin evolutionary changes in axial formulae that exclusively alter the trunk region. Overall design: RNA-seq of in vitro cultured cells along NMP differentation