Primordial germ cell deficiency in the connexin 43 knockout mouse arises from apoptosis associated with abnormal p 53 activation Richard

Abstract

INTRODUCTION The connexin multigene family encode proteins that oligomerize to form gap junction membrane channels that span the extracellular space. They allow the direct transfer of ions, metabolites and other small second messengers between neighboring cells (Bruzzone et al., 1996; White and Paul, 1999). The connexin gene Gja1 encodes a 43 kd protein known as connexin 43 or Cx43 (Goodenough et al., 1996; Sohl and Willecke, 2004), also known as 1 connexin (Kumar and Gilula, 1996), and is referred to here as Cx43 1. Studies of knockout mouse models have revealed an essential role for a number of the connexins in development and disease (White and Paul, 1999). Cx43 1 was shown to be essential in heart development, as the Cx43 1 knockout mice Gja1tm1Kdr (Cx43 1KO) die at birth due to conotruncal heart malformations and pulmonary outflow obstruction (Reaume et al., 1995). Cx43 1KO mice also displayed gonadal defects, with newborn pups exhibiting hypoplastic ovaries and testes deficient in primordial germ cells (PGCs) (Juneja et al., 1999; Roscoe et al., 2001). In mouse embryos, cytochemical detection of alkalinephosphatase activity indicated that PGCs first appear at embryonic day (E) 7.0, in the extra-embryonic mesoderm at the base of the allantois (Bendel-Stenzel et al., 1998). However, PGCs may be linage specified earlier, as PGCs emerge when epiblasts from E5.5 embryos are co-cultured with extra-embryonic ectoderm (Yoshimizu et al., 2001). From the allantois, PGCs migrate into the hindgut endoderm (E8.0), and travel along the dorsal mesentery (E9.5), finally arriving at and populating the genital ridges (E10.5-E11.5) (Bendel-Stenzel et al., 1998; McLaren, 2003). From a founding population of about ten cells at E7.0 (Ginsburg et al., 1990), PGCs rapidly expand to approximately 25,000 cells at E13.5, when gonadal differentiation begins in conjunction with sex determination (Tam and Snow, 1981). Recent studies have provided extensive evidence of an essential role for Cx43 1 in gonadogenesis. Cx43 1 is seen at all stages of ovary development (Perez-Armendariz et al., 2003) and is required for the growth and expansion of granulosa cells. Ovaries in the Cx43 1KO mice are PGC deficient (Juneja et al., 1999). In the absence of Cx43 1, granulosa cells are not functionally coupled and stop growing at an early pre-antral stage (Gittens et al., 2003). Lack of Cx43 1 restricted to the granulosa cells is sufficient to prevent the normal development of both oocyte and follicle, but chimera studies showed that Cx43 1 expression in oocytes is not required for oocytes to reach maturity (Gittens and Kidder, 2005). These findings indicate an essential role for Cx43 1 in folliculogenesis. Cx43 1 is also found at all stages of testicular development, and provides gap junctions that link germ cells with Sertoli cells (Perez-Armendariz et al., 2001). Testes isolated from Cx43 1-deficient fetuses display a ‘Sertoli cell only’ phenotype characterized by an almost complete lack of germ cells (Roscoe et al., 2001). Cx43 1KO embryos are known to be PGC deficient from E11.5, the time when genital ridges are first formed (Juneja et al., 1999). This would suggest an early requirement for Cx43 1 in germ cell development. Actively migrating PGCs are known to form extensive cell-cell contacts, such that more than 90% of the migrating PGCs are linked via cell processes (Gomperts et al., 1994). This suggests the possibility that cell-cell interactions mediated by Cx43 1 may play a role in regulating the migration and targeting of PGCs to the genital ridge. We previously showed Cx43 1 modulates the migratory behavior of two extracardiac cell populations, the cardiac neural crest (Huang et al., 1998; Sullivan et al., 1998; Xu et al., 2001) and pro-epicardial cells (Li et al., 2002). Thus it seemed plausible that the PGC deficiency of the Cx43 1KO mouse may involve a germ cell migration defect due to the loss of Cx43 1 gap Primordial germ cell deficiency in the connexin 43 knockout mouse arises from apoptosis associated with abnormal p53 activation

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@inproceedings{Francis2006PrimordialGC, title={Primordial germ cell deficiency in the connexin 43 knockout mouse arises from apoptosis associated with abnormal p 53 activation Richard}, author={J . B . Francis and Cecilia W Lo}, year={2006} }