Premature ovarian failure in nobox-deficient mice is caused by defects in somatic cell invasion and germ cell cyst breakdown

Abstract

Purpose: To understand the mechanism of premature ovarian failure (POF).

Methods: The ultrastructural (electron microscopy) analysis of primordial ovarian follicles in Nobox deficient mice.

Results: We studied, for the first time, the fate of oogonia in embryonic (prenatal) mouse ovaries and showed that the abolishment of the transition from germ cell cysts to primordial follicles in the ovaries of Nobox deficient mice is caused by defects in germ cell cyst breakdown, leading to the formation of syncytial follicles instead of primordial follicles.

Conclusions: These results indicate that POF syndrome in Nobox deficient mice results from the faulty signaling between somatic and germ line components during embryonic development. In addition, the extremely unusual and abnormal presence of adherens junctions between unseparated oocytes within syncytial follicles indicates that faulty communication between somatic and germ cells is involved in, or leads to, abnormalities in the cell adhesion program.

Fig. 1

Nobox +/− ovaries. (a, b) E17.5. Projections of somatic cells (psc) penetrating between plasma membranes of connected oocytes (oo); Golgi complex (Gc); mitochondria (m); oocyte nucleus (on). (c) P0. An intercellular bridge (ib) surrounded by broad projections of somatic cells (sc); the projections containing arrays of microfilaments (encircled); the section tangential to the bridge surface. (d) P0. Two neighboring primordial ovarian follicles; the oocytes (oo) completely separated by somatic cell projections (psc); mitochondria (m). Scale bar is equal to 1 μm

Fig. 2

Nobox −/− ovaries. (a) E16.5. A longitudinal section through intercellular bridge (ib); the absence of somatic cell projections between connected oocytes (oo); electron-dense rims of the bridge (rb); oocyte nucleus (on). (b) E17.5. A Balbiani body in the oocyte; a pair of centrioles (the centrosome, encircled) surrounded by large Golgi complexes (Gc); oocyte nucleus (on). (c, d) P0. Syncytial follicles composed of unseparated oocytes (oo) and somatic cells (asterisks). Semithin section, methylene blue. (e) E16.5. Ovaries showing the presence of intercellular bridges (Tex14, red fluorescence) between oocytes. Scale bar is equal to 1 μm in a and b, 10 μm in c and d, and 15 μm in e

Fig. 3

Nobox −/− ovaries. (a–f). P0. (a). Three adjacent oocytes from the syncytial follicle shown in Fig. 2c; Golgi complex (Gc); aggregations of mitochondria and RER cisternae (m+er); the absence of somatic cell projections between plasma membranes of neighboring oocytes. (b) Adherens junctions (arrows) between plasma membranes of somatic cells (sc) or their projections (psc) and the oocyte (oo). (c) Adherens junctions (arrows) connecting plasma membranes of adjacent oocytes (oo). (d) Three adherens junctions (arrows) connecting the tip of somatic cell projection (psc) and the oocyte plasma membrane (oo). (e) A Balbiani body (Bb) in the oocyte; centriole (encircled); Golgi complex (Gc). (f) A centriole (encircled) in the vicinity of the oocyte plasma membrane; large adherens junctions (arrows) between the membrane of the oocyte (oo) and somatic cell (sc). Scale bar is equal to 1 μm