Multiple roles of endocytosis and autophagy in intracellular remodeling during oocyte-to-embryo transition

Abstract

Fertilization is the starting point for creating new progeny. At this time, the highly differentiated oocyte and sperm fuse to form one zygote, which is then converted into a pluripotent early embryo. Recent studies have shown that the lysosomal degradation system via autophagy and endocytosis plays important roles in the remodeling of intracellular components during oocyte-to-embryo transition. For example, in Caenorhabditis elegans, zygotes show high endocytic activity, and some populations of maternal membrane proteins are selectively internalized and delivered to lysosomes for degradation. Furthermore, fertilization triggers selective autophagy of sperm-derived paternal mitochondria, which establishes maternal inheritance of mitochondrial DNA. In addition, it has been shown that autophagy via liquid-liquid phase separation results in the selective degradation of some germ granule components, which are distributed to somatic cells of early embryos. This review outlines the physiological functions of the lysosomal degradation system and its molecular mechanisms in C. elegans and mouse embryos.

Keywords: autophagy; endocytosis; fertilization; oocyte-to-embryo transition.

Figure 1.

(A) C. elegans germ line. The C. elegans hermaphrodite gonad contains a pair of U-shaped gonad arms containing a spermatheca, which accommodates sperms. A distal region of each gonad is composed of a syncytium that contains germ cell nuclei. Oocytes are formed by cellularization around the bend region of the gonad arm and growing oocytes move to the proximal region. In the most proximal region, the oocyte receives the signal from the sperm and undergoes meiotic maturation and cortical rearrangement. Mature oocytes are ovulated into the spermatheca which contains sperm and the oocytes are fertilized. The fertilized egg then moves to the uterus, completes meiosis I and II and starts embryogenesis. DTC, distal tip cell. (B) Multiple roles of endocytosis and autophagy during oocyte-to-embryo transition. Growing oocytes take up yolk components via receptor-mediated endocytosis in the proximal region. Oocytes receive a signal from the sperm and undergo lysosomal switching. Immediately after fertilization, sperm-derived paternal mitochondria and membranous organelles (MOs) are ubiquitinated at metaphase I and then eliminated by allophagy. Some populations of maternal membrane proteins are ubiquitinated at anaphase II and selectively endocytosed for degradation by the 2-cell stage. Induction of autophagy occurs at later embryonic stages again (64–100 cells). Autophagy of PGL granules also occurs in somatic cells of embryos.

Figure 2.

(A) Receptor-mediated endocytosis of yolk components. Yolk components secreted from the intestine are endocytosed by the growing oocytes. RME-2 is a yolk receptor that is recycled between the plasma membrane and endosomes to deliver yolk components to yolk granules in growing oocytes. Many proteins, including RME proteins are involved in this process. After fertilization, RME-2 is delivered to lysosomes via the multivesicular body (MVB) pathway for degradation. CHC, clathrin heavy chain; PM, plasma membrane. (B) Selective degradation of maternal membrane proteins in embryos. Some of the maternal membrane proteins (RME-2, CAV-1, CHS-1, and EGG-1) are internalized by clathrin-dependent endocytosis and delivered to lysosomes via the MVB pathway. This process depends on meiotic cell cycle progression triggered by anaphase-promoting complex/cyclosome (APC/C). Ubiquitin-conjugating enzymes (E2) such as UBC-13 and its variants, UEV-1, are involved in the ubiquitination of maternal membrane proteins. By contrast, SNB-1 and SYN-4, which are general factors regulating membrane trafficking, remain after fertilization and continue to function in embryos. PM, plasma membrane.

Figure 3.

Selective degradation of maternal membrane proteins in mouse embryos. (A) Some of the maternal membrane proteins (Glyt1a CD151, and Sypl) are selectively internalized by clathrin-dependent endocytosis by the late 2-cell stage (40 hours post fertilization) and slowly delivered to lysosomes for degradation by the 8-cell stage (54 hours post fertilization). In contrast, CD9 is partly retained on the plasma membrane or released into the perivitelline space (PVS). (B) Autophagy is induced immediately after fertilization and later stages. Lysosomal maturation appears to be initiated around the 2-cell stage.

Figure 4.

Allophagy of paternal mitochondria and MOs in C. elegans embryos. In C. elegans embryos, sperm-derived paternal mitochondria and membranous organelles (MOs) are degraded by selective autophagy called allophagy. Paternal mitochondria seem to be denatured after fertilization and are ubiquitinated at a low level. An autophagy adaptor, ALLO-1 and its binding partner IKKE-1, localize to the paternal mitochondria and recruit the autophagy factor LGG-1 for the formation of autophagy. IKKE-1 is a kinase that phosphorylates ALLO-1. MOs are heavily ubiquitinated and eliminated by allophagy in the same manner.

Figure 5.

PGL granule autophagy in C. elegans embryos. (A) P granule is a type of germ granule that is selectively distributed to the germ cell lineage during embryogenesis. P granule components in somatic cells form PGL granules (PGL-1-positive granules) and are selectively removed by autophagy. (B) SEPA-1 is an autophagy adaptor for P granule components such as PGL-1 and PGL-3. EPG-2 localizes to PGL granules via SEPA-1 and changes the property of PGL granules from a soft liquid phase to a gel state for autophagy.