| During development, motor neurons are diversified into several dozen distinct subtypes as a result of rostro-caudal patterning that drives Hox gene expression. In Chapter One, I give an overview of motor neuron diversity, molecular mechanisms that regulate Hox gene expression in the developing spinal cord, and review recent evidence on differentiation of embryonic stem (ES) cells to spinal motor neurons.;Extrinsic signals regulate rostro-caudal patterning and Hox gene expression. In Chapter Two, I demonstrate that ES cells give rise to motor neurons expressing Hox genes characteristic of brachial and thoracic spinal segments. A subset of brachial motor neurons exhibited molecular properties of limb innervating lateral motor column (LMC) neurons including their ability to acquire motor pool identities cell-autonomously.;The Cdx family of transcription factors plays an evolutionarily conserved role during caudal structure development and regulation of Hox gene expression. In Chapter 3, I provide evidence that Cdx2 is necessary and with FGF sufficient for generation of caudal brachial and thoracic motor neurons from ES cells. Wnt and FGF regulate Cdx2 expression, caudalize ES cells, and drive differentiation of brachial LMC neurons.;Settling position in the spinal cord and projections of motor axons along distinct trajectories are properties that conform to columnar subtype identity of spinal motor neurons. In Chapter Five, I demonstrate that depending on their columnar identity, ES cell derived motor neurons acquire migratory and axon pathfinding properties in vivo reminiscent of their embryonic counterparts. |
