Transcriptional mechanisms controlling motor neuron diversity and connectivity

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The control of movement relies on the precision with which motor circuits are assembled during development. Spinal motor neurons (MNs) provide the trigger to signal the appropriate sequence of muscle contractions and initiate movement. This task is accommodated by the diversification of MNs into discrete subpopulations, each of which acquires precise axonal trajectories and central connectivity patterns. An upstream Hox factor-based regulatory network in MNs defines their competence to deploy downstream programs including the expression of Nkx and ETS transcription factors. These interactive transcriptional programs coordinate MN differentiation and connectivity, defining a sophisticated roadmap of motor circuit assembly in the spinal cord. Similar principles using modular interaction of transcriptional programs to control neuronal diversification and circuit connectivity are likely to act in other CNS circuits.

Introduction

The assembly of neurons into precisely interconnected neural circuits is crucial for nervous system function and depends on the specification of defined neuronal subpopulations during development. Motor circuits are responsible for the control of movement, an animal behavior that is the final output of most nervous system activity. Initiation and execution of body movement are controlled at many levels, but all information is ultimately channeled toward motor neurons (MNs) in the spinal cord, the activation of which triggers contraction of muscles in the periphery. MNs therefore provide the exclusive action link between the nervous system and motor output. To cope with this challenging task, MN subpopulations acquire unique identities during development allowing them to receive specific connections centrally and relay this information to defined muscles peripherally.

Spinal progenitor cell differentiation is initiated by inductive signaling interactions operating through transcriptional programs [1]. As a consequence of dorso-ventral signaling, MNs acquire a unique transcriptional profile (e.g. expression of the homeodomain proteins Hb9 and Isl2) distinguishing them from spinal interneuron populations shortly after leaving the cell cycle [1, 2, 3, 4]. Recent work has begun to shed light on how distinct transcriptional networks act at postmitotic stages of differentiation to diversify MNs, the topic representing the main focus of this review. In particular, we will address how different hierarchical and parallel transcriptional programs intersect during the course of postmitotic MN differentiation to establish a unique three-dimensional motor coordinate system required to steer movement. Understanding the logic of these transcriptional control programs provides important mechanistic insights into the principles underlying the generation of a diverse array of MN subpopulations, which acquire highly specific peripheral trajectories, stereotypic cell body positions, and central connections. Moreover, we discuss how progressive transcriptional specification of MNs establishes their competence to respond to programs initiated at later differentiation steps. How these sequential genetically determined transcription factor mediated programs interact with activity-dependent processes during development has recently been reviewed elsewhere [5, 6].

Section snippets

Acquisition of motor neuron identity to accommodate target diversity

The establishment of precise connections between MNs and the muscular output system requires their strategic alignment along the body axis. In order to accommodate differences in peripheral targets throughout the body, MN number, identity, and connectivity differ significantly along the rostro-caudal axis of the spinal cord. Analyzed anatomically, MN cell bodies are organized into motor columns according to broad projection territories such as limbs (lateral motor column, LMC) or the autonomic

Cell-intrinsic and target-induced transcriptional mediators of Hox activities

The observation that Hox factors provide important instructive cues for MN diversification raises the question of how different MNs interpret and translate combinatorial Hox expression into appropriate downstream signaling cascades and effector molecules. Recent evidence suggests that Hox transcription factors function by controlling downstream modules of intermediate transcription factors that in turn orchestrate more refined aspects of MN differentiation. These intermediate transcription

Conclusions

Collectively, the studies discussed in this review provide evidence for the existence of sophisticated transcriptional networks acting in MN subpopulations at postmitotic stages to control their appropriate differentiation and incorporation into motor circuits. The functionality of different transcription factors at sequential steps of MN maturation depends on the cellular context generated by upstream events and intersects with cues encountered by motor axons on the way to their targets. The

References and recommended reading

Papers of particular interest, published over the period of the review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Thomas Jessell for numerous discussions on topics covered by this review. SDT and SA were supported by a grant from the Swiss National Science Foundation, by the Kanton of Basel-Stadt, and by the Novartis Research Foundation. JD was funded by a Burroughs Welcome Fund Career Award in Biomedical Sciences and a Whitehead Fellowship for Junior Faculty.

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