The limb bud serves as an ideal model for uncovering the molecular processes that regulate embryonic development. Over the years, studies of the limb bud have greatly advanced our comprehension of the fundamental principles, and the cellular and molecular interactions involved in the coordination of organ formation during organogenesis. In the process of limb bud development, axis polarities are established, as shown by the spatially localised expression patterns of critical regulatory genes.
In this study, using the murine hindlimb as a model, we reveal that nuclear receptor subfamily 6 group A member 1 (Nr6a1) directs early development of the hindlimb by modulating both the proximal-distal and anterior-posterior axes. Specifically, deletion of Nr6a1 leads to a loss of Fgf8 expression in the apical ectodermal ridge, a likely molecular mechanism that underlies subsequent limb truncations observed in this model. Moreover, Nr6a1 lies upstream of the key regulators known to define anterior-posterior identity, includingTbx3 and Shh. Downstream of these key factors, we show that loss of Nr6a1 leads to the loss of the normal asymmetric distal Hox gene expression and results in the ectopic expression of Hoxb13, a gene that is not expressed in wildtype hindlimbs. Collectively, our data supports Nr6a1 as crucial for proper development of the hindlimb during early stages, regulating both pre-patterning and the establishment of key axes by controlling the master regulators of limb development.