Spinal cord receives information that originates in the peripheral nerve endings and in the supraspinal motor centers. This information is integrated and used for generating a proper motor response. How does spinal cord achieve this complex integration task? The specificity of motor functions is encoded in different motor neuron subtypes that innervate distinct muscle targets. Sandwiched between the incoming information and the motor output are a multitude of premotor interneurons. How these neurons process information is not understood. Most interneurons in the spinal cord and elsewhere in the vertebrate CNS have eluded analysis because of the lack of specific markers to identify them. In transgenic mice cre-recombinase based indelible markers provide an unparalleled opportunity to study these neurons in the embryonic and adult spinal cord. Developmental studies have identified transcription factors that are expressed in subsets of interneurons, for example Lhx3. Promoters of these genes are ideal candidates for targeting cre-recombinase to select interneuron subtypes. A cre-reporter can then introduce an indelible mark in these interneurons and facilitate their identification throughout development and in the adult spinal cord. Marked and lineally related interneurons provide an opportunity to test the role of transcription factors and cell-cell interactions in cell-fate specification during development and maturation during the postnatal life. The proposed experiments will use this strategy to mark the progeny of the Lhx3+ lineage, determine the role of four transcription factors and notch-mediated cell-cell communication in cell-fate specification. Further, synaptic partners of the marked neurons and their neurotransmitter properties will be determined. The information generated from these studies will further our understanding of the spinal motor circuits and the role of interneurons in the control of motor functions in health and disease.

R01NS045106

2002-12-01

2006-11-30