Defects in the Germ Line and Gonads of Mice Lacking Connexin431

Abstract

The connexins are a family of at least 15 proteins that form the intercellular membrane channels of gap junctions. Numerous connexins, including connexin43 (Cx43), have been implicated in reproductive processes by virtue of their expression in adult gonads. In the present study, we examined the gonads of fetal and neonatal mice homozygous for a null mutation in the Gja1 gene encoding Cx43 to determine whether the absence of this connexin has any consequences for gonadal development. We found that in both sexes at the time of birth, the gonads of homozygous mutants were unusually small. This appears to be caused, at least in part, by a deficiency of germ cells. The germ cell deficiency was traced back as far as Day 11.5 of gestation, implying that it arises during early stages of germ line development. We also used an organ culture technique to examine postnatal folliculogenesis in the mutant ovaries, an approach necessitated by the fact that Gja1 null mutant offspring die soon after birth because of a heart abnormality. The results demonstrated that folliculogenesis can proceed to the primary (unilaminar) follicle stage in the absence of Cx43 but that subsequent development is impaired. In neonatal ovaries of normal mice, Cx43 could be detected in the somatic cells as early as Day 1, when primordial follicles begin to appear, supporting the conclusion that this connexin is required for the earliest stages of folliculogenesis. These results imply that gap junctional coupling mediated by Cx43 channels plays indispensable roles in both germ line development and postnatal folliculogenesis.

In utero exposure to tributyltin chloride differentially alters male and female fetal gonad morphology and gene expression profiles in the Sprague–Dawley rat

“…The presence of Cx43 gap junctions has been demonstrated by Aravindakshan and Cyr [49] to be essential for cellular communication between Sertoli cells. Cellular coordination, which is mediated by gap junctions, is crucial for the development and function of reproductive tissues [50]. It is therefore significant that these key interactions are reduced or disappear following exposure to TBT.…”

The microenvironment of the embryonic neural stem cell: Lessons from adult niches?

“…Adherens junctions are also present in the hematopoietic niche, where they anchor the HSC to the osteoblasts via N-cadherin and ␤-catenin . Gap junctions, formed by connexins and responsible for chemical and electrophysiological communication between adjacent cells, play a role in the spermatogonial niches as revealed by germ cell defects in Cx 43 Ϫ/Ϫ mice, but not in Cx 32 or Cx 40 knock-in mice (Juneja et al, 1999;Plum et al, 2000).…”

“…Soluble factors such as BMPs (Xie and Spradling, 1998;Kobielak et al, 2003;Zhang et al, 2003;Andl et al, 2004;He et al, 2004;Yamashita et al, 2005), FGFs (Kashiwakura and Takahashi, 2005), Shh (Madison et al, 2005;Crosnier et al, 2006), and Wnts (Gat et al, 1998;Korinek et al, 1998;Huelsken et al, 2001;Niemann et al, 2002;Reya et al, 2003;Willert et al, 2003) are present within the niche and can originate from support cells, stem cells themselves, or differentiated cell. Cell-to-cell contact-mediated signaling is also present in adult niches in the form of connexins (Juneja et al, 1999;Plum et al, 2000), ephrins/eph (Batlle et al, 2002;Holmberg et al, 2006) and Notch (Harada et al, 1999;Lowell et al, 2000;Conboy and Rando, 2002;Calvi et al, 2003;Conboy et al, 2003;Kumano et al, 2003;Tummers and Thesleff, 2003;Hadland et al, 2004;Fre et al, 2005;Robert-Moreno et al, 2005;van Es et al, 2005;Spradling, 2006, 2007;Song et al, 2007). These signaling mechanisms may occur between stem cells, between support cells and stem cells, and between stem cells and differentiating cells.…”

Expression of Connexin43 in mouse Leydig, Sertoli, and germinal cells at different stages of postnatal development

“…It has recently been shown that alterations in spermatogenesis, in both human (Steger et al, 1999) and mouse (Batias et al, 1999), are associated with decreased Cx43 expression in adult Sertoli cells. In addition, the number of germinal cells in fetal testis from Cx43 knock-out mice is significantly reduced (Juneja et al, 1999). Moreover, substitution of the coding region of the Cx43 gene by coding sequences of Cx40 or Cx32 is not sufficient to prevent reduction in germinal cells, and still results in infertile males due to the complete absence of secondary spermatogonia (Plum et al, 2000).…”