Disruption of Iqsec1 in mice leads to embryonic lethality with reduced large apical vacuoles in the visceral endoderm

FEBS Lett. 2025 Feb;599(4):581-591. doi: 10.1002/1873-3468.15058. Epub 2024 Nov 19.

Abstract

Iqsec1 (IQ motif and Sec7 domain-containing protein 1), also known as BRAG2 (Brefeldin A-resistant Arf-GEF 2), is a guanine nucleotide exchange factor that regulates membrane trafficking, cytoskeletal organization, and signal transduction by activating class II and III ADP-ribosylation factors. To investigate the physiological role of Iqsec1 at the whole animal level, we generated Iqsec1-deficient mice using CRISPR/Cas9-mediated gene editing. Nearly all Iqsec1-/- mice (99%) exhibited embryonic lethality with severe growth retardation. Electron microscopy revealed that Iqsec1-/- embryos at embryonic day 8.5 lacked large apical vacuoles in visceral endoderm cells of the yolk sac, compared with controls. These findings suggest that Iqsec1 plays a critical role in embryogenesis, likely through regulation of membrane trafficking in visceral endoderm cells.

Keywords: ADP‐ribosylation factor; BRAG2; Iqsec1; guanine nucleotide exchange factor; lysosome; visceral endoderm.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems
  • Embryo Loss* / genetics
  • Embryo Loss* / pathology
  • Embryo, Mammalian / metabolism
  • Embryonic Development / genetics
  • Endoderm* / metabolism
  • Endoderm* / pathology
  • Endoderm* / ultrastructure
  • Female
  • Guanine Nucleotide Exchange Factors* / deficiency
  • Guanine Nucleotide Exchange Factors* / genetics
  • Guanine Nucleotide Exchange Factors* / metabolism
  • Mice
  • Mice, Knockout
  • Vacuoles* / genetics
  • Vacuoles* / metabolism
  • Vacuoles* / pathology
  • Vacuoles* / ultrastructure
  • Yolk Sac / metabolism
  • Yolk Sac / ultrastructure

Substances

  • Guanine Nucleotide Exchange Factors