Our brain is composed of thousands of neuronal types interconnected with extraordinary specificity to form precisely arranged neural circuits essential for normal function of the nervous system. Such neural circuits are a common feature of even the simplest nervous systems but how they are established still remains one of the key questions of developmental neurobiology. A remarkable example of neuronal organization are the somatotopic maps that preserve the contiguity from one neuronal nucleus to another. A classic pattern of somatotopic organization is the retinotectal connectivity where neighbouring retinal neurons make synaptic connections with neighbouring tectal neurons. However, our understanding of how nervous system somatotopy develops has been hindered by the fact that most neural circuits studied are very complex.
In contrast, a simple, binary organization is apparent in the arrangement of the cell bodies and axons of motor neurons of the lateral motor column (LMC) of the vertebrate spinal cord. The somatotopic organization of this system is evident in myotopy defined by the correlation between the position of motor neuron cell bodies and the position of their target muscles: motor neurons located within the medial LMC (LMCm) innervate ventral limb muscles, whereas motor neurons located within the lateral LMC (LMCl) innervate dorsal muscles. These observations make it a very attractive system in which a detailed molecular account of formation of a simple neuronal circuit remains attainable. Furthermore, our understanding of the fundamental principles governing the assembly of this circuit raises the possibility of significantly advancing our understanding of phenomena underlying motor system disease and injury.
LMC myotopy emerges through two binary developmental choices: after birth in the ventricular zone, (1) LMC axons select either a dorsal or a ventral limb trajectory, as (2) LMC motor neuron cell bodies migrate either into a lateral or a medial position within the ventral spinal cord. The simple nature of this system makes it very attractive for studies aiming at a molecular description of development of somatotopy in the nervous system. The overall goal of my laboratory is the development of a molecular model describing the initial steps in the assembly of somatotopy in a simple neural circuit composed of two spinal motor neuron subtypes whose axons innervate two distinct muscle groups in the limb and whose cell bodies occupy two discrete locations within the spinal cord.
Aim 1: Identify novel effector molecules controlling LMC axonal projection. My studies have shown that the Lim1, Isl1 and Lmx1b LIM homeodomain transcription factors act in motor neurons and limb mesenchyme to control the trajectory of LMC motor axons. These transcription factors most likely influence LMC axonal projections by controlling the expression of specific axon guidance cues and their receptors. My laboratory is currently studying the role of several such molecular effectors.
Aim 2: Determine how Lim1 and Isl1 control the mediolateral position of LMC cell bodies. Lim1 and Isl1 expression in LMC motor neurons also affects the position LMC motor neuron cell bodies within the spinal cord, suggesting that these transcription factors control the expression of effectors of cell migration. My laboratory is currently attempting to identify such effectors.
Aim 3: Develop novel tools to study the specification of LMC somatotopy. To visualize the development of LMC motor neurons and their axonal projections in real time, my laboratory is currently developing imaging tools that will enable us to follow the development of LMC myotopy in in vitro cultures.