Transcription factor mechanisms guiding motor neuron differentiation and diversification

Abstract

The embryonic generation of motor neurons is a complex process involving progenitor patterning, fate specification, differentiation, and maturation. Throughout this progression, the differential expression of transcription factors has served as our road map for the eventual cell fate of nascent motor neurons. Recent findings from in vivo and in vitro models of motor neuron development have expanded our understanding of how transcription factors govern motor neuron identity and their individual regulatory mechanisms. With the advent of next generation sequencing approaches, researchers now have unprecedented access to the gene regulatory dynamics involved in motor neuron development and are uncovering new connections linking neurodevelopment and neurodegenerative disease.

Figure 1. Motor Neuron Organization in the CNS

(A) Embryonic progenitors in the ventricular zone are patterned into discrete dorsal-ventral domains by opposing morphogen gradients. Motor neurons are generated from the ventral pMN domain. V = ventricle, Shh = Sonic Hedgehog, RA = Retinoic Acid. (B) Post-mitotic MNs are organized into motor columns that project to muscles in the limbs (LMC), trunk (MMC), intercostal muscles (HMC), or sympathetic ganglia (PMC). (C) Medial and lateral divisions of the LMC project to ventral and dorsal limb muscles, respectively. Within these divisions, motor pools innervate specific muscle groups.

Figure 2. In-vitro Motor Neuron Generation

(A) Pluripotent ESCs or iPSCs can be differentiated into MNs in-vitro through multiple protocols. Induced neuronal differentiation relies on the delivery of exogenous signaling molecules such as retinoic acid (RA) and Shh pathway agonists (SAG), mirroring embryonic development. MNs can also be differentiated by the forced expression of terminal MN TFs for direct neural programming. (B) RNA sequencing experiments have recently revealed that differentiation via direct neural programming (red circles) versus induced neuronal differentiation (blue circles) can take distinct transcription paths; however, their terminal gene expression patterns are largely convergent.