Embryonic arrest at midgestation and disruption of Notch signaling produced by the absence of both epsin 1 and epsin 2 in mice

Abstract

Epsins are endocytic adaptors with putative functions in general aspects of clathrin-mediated endocytosis as well as in the internalization of specific membrane proteins. We have now tested the role of the ubiquitously expressed epsin genes, Epn1 and Epn2, by a genetic approach in mice. While either gene is dispensable for life, their combined inactivation results in embryonic lethality at E9.5-E10, i.e., at the beginning of organogenesis. Consistent with studies in Drosophila, where epsin endocytic function was linked to Notch activation, developmental defects observed in epsin 1/2 double knockout (DKO) embryos recapitulated those produced by a global impairment of Notch signaling. Accordingly, expression of Notch primary target genes was severely reduced in DKO embryos. However, housekeeping forms of clathrin-mediated endocytosis were not impaired in cells derived from these embryos. These findings support a role of epsin as a specialized endocytic adaptor, with a critical role in the activation of Notch signaling in mammals.cell signaling ͉ endocytosis ͉ gene targeting

Selective high-level expression of epsin 3 in gastric parietal cells, where it is localized at endocytic sites of apical canaliculi

“…The much broader expression of epsin 1 and 2 ( Fig. 1B) (11) confirmed the isoform specificity of the anti-epsin 3 antibodies, which was further validated by the absence of immunoreactivity in the corresponding tissues obtained from an epsin 3 knock-out (KO) mouse ( Fig. 1 A and B) (see below).…”

“…Most studies to date have focused on epsin 1 and 2, which are concentrated in the brain, but have broad tissue distribution (3,10,11). Little is known about epsin 3, except that it was reported to be expressed, nearly exclusively, in immature keratinocytes (12).…”

Role of Recycling, Mindbomb1 Association, and Exclusion from Lipid Rafts of Delta-like 4 for Effective Notch Signaling To Drive T Cell Development

“…1), although neur1 was detected at very low levels. In addition to the E3 ubiquitin ligases, mammalian homologs of liquid facets (epsin) and dynamin (30,31) have been shown to be involved in the endocytosis process of Notch ligands, and among these epsin1, epsin2, and dynamin2 are expressed in the OP9 cells. These data show that the OP9 cells express the endocytic machinery required for efficient and effective Notch ligand endocytosis and that the OP9 cells are suitable for assessing the requirement of Dll1 and Dll4 endocytosis in T cell development.…”

Mastermind-like 1 (MamL1) and mastermind-like 3 (MamL3) are essential for Notch signaling in vivo

“…In mammals, the Hes and Hesr (also known as Hey, Herp, Hrt, CHF or gridlock) families are among the primary target genes of the Notch signaling pathway (Bray, 2006;Kopan and Ilagan, 2009). Mice deficient in one of several essential elements in this signaling pathway die in midgestation with distinctive defects: defective vascular remodeling, aberrant somitogenesis and enhanced neurogenesis (Barsi et al, 2005;Chen et al, 2009;de la Pompa et al, 1997;Donoviel et al, 1999;Hartmann et al, 2002;Herreman et al, 1999;Koo et al, 2005;Li et al, 2003;Oka et al, 1995;Serneels et al, 2005;Shi and Stanley, 2003). These are considered to be the panNotch phenotypes.…”