Stem Cell Derived Motoneurons to study motor neuron development

The ability to move is one of the most fundamental traits shared by all animals and is essential for survival. Even the simplest forms of movement, such as those required for crawling, require exquisite control of different muscle groups by the nervous system to ensure proper alternating contractions of flexor and extensor muscles. The nervous does not only have to activate and de-activate muscle groups for precise movements, it must also determine how much activation is required to generate the proper amount of force. How precise control of movement is established during development remains poorly understood. From a neuromuscular point of view, activation of precise muscle groups begins with selective guidance of specific motoneuron subgroups to their correct muscle targets. Precise level of activation begins with the development of motoneuron characteristics that allow for a systematic, smooth gradation in force.

Studies have shown that motor axons are guided to the muscles target(s) using a series of guidance molecules. While the identities of many of the molecules involved have been identified, the cellular mechanisms controlling their expression and downstream pathways activated are less well understood. This proposal will examine how the LIM transcription factor Lhx1 regulates selective motor axon guidance of LMCl motoneurons to innervate dorsal hindlimb muscles. Thus, we propose to use motoneurons derived from embryonic stem cells and mouse genetics as complementary model systems to examine whether Lhx1 regulates axon targeting. We will also examine what intracellular signaling molecules are activated when the axons confront guidance molecules known to be involved in their selective targeting.

One of the most established principle in motor control is known as the “size principle”. The size principle enables the smooth gradation in contraction as more force is required and ensures that motor units are recruited in a sequential manner based on size and fatigability. Even though the size principle is one of the most fundamental principles in motor control, very little is known about how, or even when, the distinct anatomical properties (e.g. cell body size and innervation ratio) of different motor units form during development. Based on a proteomic screen between motoneurons differing in size we hypothesis that the size principle is regulated, at least in part, by signaling through the Lats2/Yap signaling pathway. We will test this hypothesis by generating mice specifically lacking Lats2/Yap signaling in post-mitotic developing motoneurons. Using a combination of morphological and electrophysiological techniques we will test how the loss of Lats2/Yap signaling in motoneurons affects the emergence of the size principle.

These studies are novel as they will examine to important properties for precise motor control; how the neural circuit is formed and how intrinsic properties of the circuit development to ensure its proper function.