Figure 2. A model for the diversification of spinal motor neuron subtypes during vertebrate evolution.

Lower branch. Inductive signaling along the dorsoventral axis of the neural tube involves the graded actions of sonic hedgehog (Shh) and Wnt proteins (not shown) secreted by the floor plate and adjacent ventral cells, and the patterned expression of homeodomain (HD) proteins by ventral progenitor cells and post-mitotic neurons. This dorso-ventral patterning pathway recruits expression of the LIM homeodomain proteins Lhx3 and Lhx4 by newly generated motor neurons, assigning a median motor column (MMC) – like identity. In primitive ancestral vertebrates such as the lamprey and hagfish the dominance of this inductive pathway confers all motor neurons with a MMC fate, providing the neural substrate for undulatory locomotor behaviors.

Upper branch. Over the course of ∼500 million years of evolution, rostro-caudal inductive signals mediated by retinoids (RA) and fibroblast growth factors (FGF) establish the patterned expression of Hox homeodomain proteins in motor neuron progenitors and post-mitotic motor neurons. The engagement of Hox transcription factors, and an essential Hox accessory factor, FoxP1, drives motor neuron columnar and pool diversification, resulting in the formation of lateral motor column (LMC) neurons and their resident motor pools. This diversification process permits the spinal motor system to innervate the more complex set of peripheral motor targets that characterizes higher vertebrates and underlies intricate tetrapod gait patterns.

The key intermediate step in this diversification process is presumed to involve the attenuation of non-canonical Wnt signaling, permitting the generation of motor neurons that lack Lhx3 and Lhx4 expression and progress to a hypaxial motor columnar (HMC) fate (not shown). This ground-state HMC-like column provides the neuronal substrate for the actions of the Hox/FoxP1 transcriptional program. For details, see text and ref 26.