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First published online November 21, 2008
doi: 10.1242/10.1242/dev.026807

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A differential developmental pattern of spinal interneuron apoptosis during synaptogenesis: insights from genetic analyses of the protocadherin- gene cluster

¹ Department of Biology, The University of Iowa, Iowa City, IA 52242, USA.
² Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, IL 60208, USA.
³ Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO 63110, USA.
⁴ Neuroscience Graduate Program, The University of Iowa, Iowa City, IA 52242, USA.

^* Author for correspondence (e-mail: joshua-weiner{at}uiowa.edu)

Accepted 30 October 2008

Although the role of developmental apoptosis in shaping the complement and connectivity of sensory and motoneurons is well documented, the extent to which cell death affects the 13 cardinal classes of spinal interneurons is unclear. Using a series of genetic manipulations in vivo, we demonstrate for the first time a differential pattern of developmental apoptosis in molecularly identified spinal interneuron populations, and implicate the adhesion molecule family encoded by the 22-member protocadherin- (Pcdh-) gene cluster in its control. In constitutive Pcdh- null mouse embryos, many interneuron populations undergo increased apoptosis, but to differing extents: for example, over 80% of En1-positive V1 neurons are lost, whereas only 30% of Chx10-positive V2a neurons are lost and there is no reduction in the number of V1-derived Renshaw cells. We show that this represents an exacerbation of a normal, underlying developmental pattern: the extent of each population's decrease in Pcdh- mutants is precisely commensurate both with the extent of its loss during normal embryogenesis and with the extent of its increase in Bax^-/- mice, in which apoptosis is genetically blocked. Interneuron apoptosis begins during the first wave of synaptogenesisis in the spinal cord, occurring first among ventral populations (primarily between E14 and E17), and only later among dorsal populations (primarily after P0). Utilizing a new, conditional Pcdh- mutant allele, we show that the -Pcdhs can promote survival non-cell-autonomously: mutant neurons can survive if they are surrounded by normal neurons, and normal neurons can undergo apoptosis if they are surrounded by mutant neurons.

Key words: Ventral horn, Spinal cord, Apoptosis, Synapse formation, Interneurons, Programmed cell death

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