Peripubertal requirement of Tsg101 in maintaining the integrity of membranous structures in mouse oocytes

As a component of Endosomal Sorting Complex Required for Transport (ESCRT) complex I, the tumor susceptibility gene 101 (Tsg101) carries out multiple functions. In this work, we report that oocyte-specific deletion of tumor susceptibility gene 101 (Tsg101) leads to age-dependent oocyte demise in mice.

Tsg101 floxed mice (Tsg101^f/f ) were bred with Zp3^cre transgenic mice to examine oocyte-specific roles of Tsg101. Multiple cellular and molecular biological approaches were taken to examine what leads to oocyte demise in the absence of Tsg101.

The death of oocytes from Zp3^cre /Tsg101^f/f (Tsg101^d/d thereafter) mice showed a strong correlation with sexual maturation, as gonadotropin-releasing hormone antagonist injections improved the survival rate of oocytes from 5-week-old Tsg101^d/d mice. Maturation of oocytes from prepubertal Tsg101^d/d mice proceeded normally, but was largely abnormal in oocytes from peripubertal Tsg101^d/d mice, showing shrinkage or rupture. Endolysosomal structures in oocytes from peripubertal Tsg101^d/d mice showed abnormalities, with aberrant patterns of early and late endosomal markers and a high accumulation of lysosomes. Dying oocytes showed plasma membrane blebs and leakage. Blockage of endocytosis in oocytes at 4°C prevented cytoplasmic shrinkage of oocytes from Tsg101^d/d mice until 9 h. The depletion of tsg-101 in Caenorhabditis elegans increased the permeability of oocytes and embryos, suggesting a conserved role of Tsg101 in maintaining membrane integrity.

Collectively, Tsg101 plays a dual role in maintaining the integrity of membranous structures, which is influenced by age in mouse oocytes.