Fertilization and First Mitosis/Cell Division

Successful fertilization depends on a number of different factors in which oocyte and sperm quality are critically important. In non-rodent mammalian species, the sperm’s centriole-centrosome complex is essential for nucleating and organizing the sperm aster, zygote aster, first mitotic apparatus and all subsequent mitoses during embryo development (Figure 10.1) (Sathananthan 1992; Sathananthan et al., 1996,2001; reviewed in Schatten and Sun 2011b, 2015a,b). After sperm incorporation, the sperm’s centriole-centrosome complex recruits centrosomal proteins from the oocyte, a process that involves dynein functions to help transport of oocyte-derived centrosomal proteins along microtubules to the centrosome core structure (Payne et al., 2003; reviewed in Schatten and Sun 2011b, 2015a,b). Pathologies in the sperm’s centriole-centrosome complex or oocyte-derived centrosome defects can lead to fertilization failures or developmental abnormalities (Rawe et al., 2000, 2002; Rawe and Chemes 2009; Schatten and Sun 2015a,b).

While numerous papers are available on mouse fertilization (oftentimes generalized as mammalian fertilization) it is important to re-emphasize that fertilization in the mouse is based on different mechanisms that do not compare to mechanisms used by non-rodent mammals including humans. This fact had already been recognized many years ago when it was attempted to use mouse oocytes to test human sperm functions in heterologous fertilization assays. These experiments were discontinued when it was recognized that rodent and non-rodent fertilization mechanisms are incompatible. It was recognized that non-rodent mammalian sperm contributed the centriole-centrosome complex as essential component for successful fertilization while mouse fertilization does not require a centriole-centrosome complex for fertilization. In fact, the mouse oocyte does not even tolerate centrioles, as centrioles are destroyed in the mouse oocyte, as had already been shown by Szollosi et al., (1972). In non-rodent mammals including the bovine, porcine, horse, and human the sperm contains a pair of perpendicularly oriented centrioles, termed proximal and distal centriole. The distal centriole is associated with the sperm tail while the proximal centriole is surrounded by a sparse amount of centrosomal proteins that increases after sperm incorporation into the ooplasm to assume microtubule organizing functions resulting in sperm aster, zygote aster, and mitotic apparatus formations (reviewed in Schatten and Sun 2011a,b; 2015a,b). The majority of centrosomal proteins become recruited from the ooplasm to compose a zygotic centrosome that becomes division competent during the first embryonic cell cycle. Duplication of the centriole-centrosome complex occurs during the S-phase and enables the centriole-centrosome complex to separate and localize to the mitotic poles of first embryonic mitosis (reviewed in Schatten 2008; Schatten and Sun 2011b).

As mentioned previously, oocyte and sperm quality are important for successful fertilization. Selection of high-quality sperm and high-quality oocytes for IVF is addressed excellently in several chapters of this book (Simon et al., 2016; Combelles 2016) and will not be addressed in this section. Oocyte abnormalities have been addressed in Section 10.3 and in previous review papers (Schatten and Sun 2011a,b; 2015a,b) while specific sperm pathologies related to centriole or centrosome abnormalities have been well reviewed by Chemes (2000) and Chemes and Rawe (2003). Here we will focus on post-insemination centrosome and cytoskeletal regulation that is critical for cell cycle progression and embryo development.

The importance of one and only one centrosome complex contributed by one sperm had already been recognized by Theodore Boveri (1901) who used sea urchin eggs to show that fertilization with two sperm (dispermy) or more sperm (trispermy or polyspermy) resulted in multipolar mitosis and division abnormalities. We now know that this is also the case for human fertilization, mitosis, and cell division. By using molecular methods, we also now know that cases of infertility as well as subfertility are associated with decreased centrosome functions (Hinduja et al., 2010; reviewed by Schatten and Sun 2011b).

While we do know that centrin and a small amount of у-tubulin is associated with the sperm centriole-centrosome complex before fertilization we still know only little about other centrosomal components surrounding the sperm centriole and the regulation of centrosome growth after fertilization. We know that у-tubulin quantitatively increases around the sperm centrosome complex after fertilization by recruiting additional у-tubulin from the ooplasm. As mentioned previously, insufficient у -tubulin and centrin have both been correlated with decreased fertilization success (Hinduja et al., 2010) and decrease in sperm aster formation after fertilization (Navara et al., 1996). As mentioned previously, one potentially interesting still unexplored nuclear and centrosome-associated protein, NuMA, may play a role in fertility problems related to failure of sperm decondensation after fertilization. NuMA is a component of the nuclear matrix that becomes clearly detectable in the decondensing sperm nucleus after fertilization, as analyzed by immunofluorescence microscopy (reviewed in Sun and Schatten, 2006; Liu et al., 2006; Alvarez-Sedo et al., 2011). We have shown failure in nuclear decondensation in human oocytes that did not develop following sperm incorporation (Alvarez-Sedo et al., 2011) which may be related to failure in NuMA functions.

Nuclear and centrosomal proteins undergo cell cycle-specific regulations and are well synchronized during cell cycle progression to coordinate spindle formation and chromosome segregation. NuMA needs to be regulated precisely to serve coordinated nuclear and centrosome functions. However, we do not yet understand the factors by which NuMA is regulated in the pronuclei and we do not yet know the factors that play a role in NuMA dispersion from the pronuclei to the ooplasm and subsequent associations with the MI and MII spindles. As mentioned in Sections 10.2 and 10.3, in unfertilized non-rodent mammalian oocytes including human oocytes, NuMA is localized to the poles of the MI and MII spindles. After fertilization, NuMA becomes localized to the female pronucleus after completion of meiosis II. As mentioned above, after fertilization, NuMA becomes detectable by immunofluorescence microscopy in the decondensing sperm pronucleus and disperses into the ooplasm after pronuclear apposition and nuclear envelope breakdown (NEBD). Failures in NuMA functions have recently been shown in human oocytes and in sperm that failed to decondense while displaying abnormal NuMA immunofluorescence staining patterns (Alvarez-Sedo et al., 2011; Schatten et al., 2012). So far, research on NuMA regulation has only been reported for somatic cells in which cyclin B plays a major role (reviewed in Sun and Schatten 2006; Schatten and Sun 2011a,b) but not yet for embryonic cells that may require factors for regulation that are different from somatic cells (reviewed in Schatten and Sun 2011b). As NuMA directly links nuclear functions with mitotic centrosome functions more studies are needed to analyze NuMA regulation in sperm, in oocytes, and in embryo cells to extent on previous studies in fertilized eggs and cloned embryos (Zhong et al., 2005).

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