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First published online 3 August 2006
doi: 10.1242/dev.02506

Development 133, 3451-3460 (2006)
Published by The Company of Biologists 2006
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Primordial germ cell deficiency in the connexin 43 knockout mouse arises from apoptosis associated with abnormal p53 activation

Richard J. B. Francis and Cecilia W. Lo*

Laboratory of Developmental Biology, National Heart Lung and Blood Institute, National Institutes of Health, Building 50/Room 4537, 9000 Rockville Pike, Bethesda, MD 20892, USA.

* Author for correspondence (e-mail: loc{at}nhlbi.nih.gov)

Accepted 21 June 2006

Connexin 43 knockout (Cx43{alpha}1KO) mice exhibit germ cell deficiency, but the underlying cause for the germ cell defect was unknown. Using an Oct4-GFP reporter transgene, we tracked the distribution and migration of primordial germ cells (PGCs) in the Cx43{alpha}1KO mouse embryo. Analysis with dye injections showed PGCs are gap-junction-communication competent, with dye coupling being markedly reduced in Cx43{alpha}1-deficient PGCs. Time-lapse videomicroscopy and motion analysis showed that the directionality and speed of cell motility were reduced in the Cx43{alpha}1KO PGCs. This was observed both in E8.5 and E11.5 embryos. By contrast, PGC abundance did not differ between wild-type and heterozygous/homozygous Cx43{alpha}1KO embryos until E11.5, when a marked reduction in PGC abundance was detected in the homozygous Cx43{alpha}1KO embryos. This was accompanied by increased PGC apoptosis and increased expression of activated p53. Injection of {alpha}-pifithrin, a p53 antagonist, inhibited PGC apoptosis and prevented the loss of PGC. Analysis using a cell adhesion assay indicated a reduction in ß1-integrin function in the Cx43{alpha}1KO PGCs. Together with the abnormal activation of p53, these findings suggest the possibility of anoikis-mediated apoptosis. Overall, these findings show Cx43{alpha}1 is essential for PGC survival, with abnormal p53 activation playing a crucial role in the apoptotic loss of PGCs in the Cx43{alpha}1KO mouse embryos.

Key words: PGC, Cx43, Migration, p53, ß1 integrin, Apoptosis, Mouse


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