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 understanding of the fundamental principles and the cellular and molecular interactions that coordinate organ formation during organogenesis. During limb bud development, axial 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 hindlimb development by modulating both the proximal–distal and anterior–posterior axes. Specifically, deletion of Nr6a1 leads to loss of Fgf8 expression in the apical ectodermal ridge (AER), a likely molecular mechanism underlying the subsequent limb truncations observed in this model. Moreover, Nr6a1 lies upstream of key regulators that define anterior–posterior identity, including Tbx3 and Shh. Downstream of these factors, we show that loss of Nr6a1 disrupts normal asymmetric distal Hox gene expression and results in ectopic expression of Hoxb13, a gene not expressed in wild-type hindlimbs. Collectively, our data support Nr6a1 as crucial for proper hindlimb development during early stages, regulating both pre-patterning and the establishment of key axes by controlling master regulators of limb development.