Date of Degree
PhD (Doctor of Philosophy)
Joshua A. Weiner
Protocadherins (Pcdhs) are a large family of adhesion molecules which have structure similar to that of classical cadherins. About 60 Pcdh genes are organized into three clusters (-á,- â and- ã), which are arranged contiguously on a single chromosome in mammals. Mice in which the 22-gene Pcdh- ã locus has been deleted die within a few hours of birth and show defects in movement and reflexes, extensive neurodegeneration in the spinal cord, and loss of synapses. Further studies have shown that loss of ã-Pcdhs has a primary effect on the formation or maintenance of synapses that can be dissociated from its role in cell survival. Extensive apoptotic cell death observed during the late embryonic development period in the spinal cord of the Pcdh- ã del/del mutant mice is confined to molecularly distinct populations of spinal interneurons. Analysis of cell death patterns during development of spinal cords from wild-type, the Pcdh- ã del/del and Bax -/- mice in which cell death is blocked due to deletion of a proapoptotic protein, confirmed that loss of ã-Pcdhs exacerbates a previously undocumented normal developmental pattern of spinal interneuron apoptosis. Restricted disruption of the Pcdh- ã gene cluster within specific neuronal populations suggested that ã-Pcdhs can control neuronal survival in a non-cell autonomous manner. Loss of ã-Pcdhs also resulted in an aberrant pattern of 1a proprioceptive sensory afferent (1aPSA) terminals in the spinal cord. In Pcdh- ã del/del mice the area occupied by 1aPSA terminals per motor neuron increased by 150% over the control with a corresponding reduction of 30% in the area occupied by 1aPSA terminals on the ventral interneurons. Further analysis in the Pcdh- ã del/del; Bax-/- double mutants, as well as in mouse lines in which Pcdh- ã gene cluster disruption was confined to specific neuronal subpopulations, suggested that this aberrant pattern was a result of both the increased loss of ventral interneurons in mutants, as well as a cell autonomous requirement of ã-Pcdhs in the 1aPSA and their intermediate target ventral interneurons. These studies provide evidence that the ã-Pcdhs mediate homophilic interactions that are important for the formation of multiple neuronal circuits, and are critical molecules in the regulation of interneuron survival and CNS development.
adhesion molecules, apoptosis, interneurons, neuronal circuits, spinal cord, synapse formation
Copyright 2009 Tuhina Prasad