The vertebrate spinal cord is a complex structure containing many different classes of motor- and inter-neurons that coordinate motor function. During development, these neurons are produced from progenitor cells positioned medially along the dorsoventral axis of the neural tube that migrate laterally as they exit the cell cycle. Motor neurons are then organized in a hierarchical fashion, first being arranged in columns that innervate large target areas (like back musculature and limbs) and further arranged in motor pools that innervate particular muscles (like biceps and triceps). Motor columns are specified by their combinatorial expression of lim homeodomain transcription factors, while the motor pools appear to be specified by their combinatorial expression of hox and ets families of transcription factors. Little is known however about how these transcription factors control the guidance of axons to their proper targets, although presumably they control the expression of cell surface receptors that respond to signals in the periphery.

HB9 (green), Isl1/2 (red), Lhx3 (blue) Triple Stain

Over the past several years, we have been utilizing mouse genetic and chick gain of function approaches to understand the fundamental principles that control gene expression in the developing spinal cord with the ultimate goal of understanding both the cell intrinsic (genetic) and extrinsic factors that play a role in this process. Mouse knockouts of key transcription factors (including Isl-1 and HB9) have been crucial to our understanding of how motor neurons are specified in the developing neural tube, and have begun to give us insight into how these key transcription factors function to control target gene expression.

Recently, we have developed an in vitro ES cell model of motor neuron differentiation that will allow us to generate pure populations of neurons in large enough numbers to perform experiments that are difficult or impossible with the limited cellular material of early embryos. We hope to use this approach to address a wide range of questions including:

1. What are the transcriptional changes that accompany progressive differentiation of early neural progenitors to more restricted motor neuron fates?
2. How do changes in chromatin structure contribute to cell fate plasticity?
3. How does cell polarity function in cell fate decisions?

In addition, we have begun to explore the use of ES derived neurons to model human diseases such as ALS, SMA, and post-polio syndrome, with the hope of understanding the biochemical mechanisms that underlie their pathology.

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