Journal of Animal Reproduction and Biotechnology 2021; 36(4): 183-188
Published online December 31, 2021
https://doi.org/10.12750/JARB.36.4.183
Copyright © The Korean Society of Animal Reproduction and Biotechnology.
Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea
Correspondence to: Jongki Cho
E-mail: cjki@cnu.ac.kr
In vitro maturation (IVM) of oocytes is the procedure where the immature oocytes are cultivated in a laboratory until they are mature. Since IVM oocytes generally have low developmental competence as compared to those matured in vivo, development of an optimal IVM culture system by fine-tuning culture conditions is crucial to maintain high quality. In-depth knowledge and a deep understanding of the in vivo physiology of oocyte maturation are pre-requisites to accomplish this. Within ovarian follicles, various signaling pathways that drive oocyte development and maturation regulate interaction between oocytes and surrounding somatic cells. This review discusses the sonic hedgehog (SHH) signaling pathway, which has been demonstrated to be intimately involved in folliculogenesis and oocyte maturation. Advances in elucidating the role of the SHH signaling pathway in oocyte maturation will aid attempts to improve the current inferior in vitro oocyte maturation system.
Keywords: in vitro oocyte maturation, ovarian follicle, sonic hedgehog signaling
Oocyte maturation is a physiological process that precedes and is essential for successful fertilization and subsequent embryonic development (Lonergan and Fair, 2016). This process is initiated a few days prior to ovulation and involves progressive changes in ovarian follicles. These include preantral to early antral transition (Palma et al., 2012) and eventual acquisition of competence to resume meiosis and fertilizability (Paulini et al., 2014). Oocyte maturation is characterized by both nuclear and cytoplasmic maturation. The former is a complicated process that includes the resumption of meiosis post luteinizing hormone (LH) surge or oocyte release from a follicle (Luciano and Sirard, 2018). Mammalian oocytes enter the early stages of meiosis during fetal life but remain arrested at prophase I until they become committed to ovulation in response to an LH surge (Grøndahl, 2008). Meiotic resumption induced by the LH surge is further stalled at metaphase II (Lonergan and Fair, 2016) which is then completed following fertilization (GGrøndahl, 2008). In contrast, cytoplasmic maturation is associated with organelle reorganization and storage of mRNAs, proteins, and transcription factors that are requisites for early embryonic development (Ferreira et al., 2009).
The functional unit of the ovary i.e. the ovarian follicle, consists of three types of cells: an oocyte, granulosa cells, and theca cells that provide an appropriate developmental environment for oocytes (Gougeon, 1996). Growing ovarian follicles demonstrate a bidirectional communication between the oocyte and surrounding somatic cells that is essential for appropriate proliferation and differentiation (Nilsson and Skinner, 2001). These communications are regulated by several classical signaling pathways, including the Wnt, insulin, Notch, and hedgehog (HH) pathways (Li et al., 2021). Wnt signaling pathway activation by Wnt2 and Wnt4 plays a crucial role in normal ovarian follicle development by promoting granulosa cell proliferation (Boyer et al., 2010; Wang et al., 2010). The insulin signaling pathway regulates follicle development in the later stages of oocyte growth and promotes oocyte development by either upregulating the binding efficacy of LH to receptors or the number of receptors itself (Das and Arur, 2017). The Notch signaling pathway is known to regulate granulosa cell proliferation, since treatment with a Notch signaling inhibitor resulted in a significant decreased in their number (Jing et al., 2017). Lastly, the HH signaling pathway has been postulated to be a target signaling pathway in ovarian follicle development, since expression of HH ligands at the primary follicle stage is well established (Wijgerde et al., 2005).
A comprehension of the signaling pathways involved in ovarian development will help design better strategies for the generation of higher quality IVM oocytes. This article discusses the sonic hedgehog (SHH) signaling pathway, which has been reported to be involved in folliculogenesis and oocyte maturation. We have further placed a special emphasis on the application of SHH-induced IVM systems owing to the widespread use of IVM oocytes both in research and in the production of genetically engineered animals via assisted reproductive technologies.
HH signaling was first discovered in
All components of the HH signaling pathway including the ligands (
The SHH signaling pathway is a complex signal transduction mechanism that controls precisely regulated developmental processes (Choudhry et al., 2014). Signal transduction via this pathway is initiated by the binding of SHH protein in an autocrine and/or paracrine fashion (Handrigan and Richman, 2010) and ultimately coordinates cell proliferation and differentiation in various cell types (Enomoto-Iwamoto et al., 2000; Osawa et al., 2006; Salda?a et al., 2016). However, the evidence that the SHH signaling pathway controls the development of ovarian follicles is of particular interest (Russell et al., 2007), since folliculogenesis and oocyte maturation proceed together until ovulation (Kidder and Vanderhyden, 2010). Several studies have demonstrated an association between SHH signaling pathway and oocyte maturation
Table 1 . The role of sonic hedgehog (SHH) signaling pathway in
Supplement | Species | Effects | Preimplantation embryonic development | References |
---|---|---|---|---|
Recombinant SHH protein | Pig | Increased oocyte nuclear maturation, cyclin B1 content, ERK1/2 phosphorylation, and intracellular calcium release | Enhanced cleavage, blastocyst formation rates, and total cell number after PA | (Nguyen et al., 2009) |
Recombinant SHH protein | Goat | Increased oocyte nuclear maturation and ERK1/2 phosphorylation | Enhanced blastocyst formation rate and | (Wang et al., 2017) |
Resveratrol | Pig | Increased cumulus cell expansion, oocyte nuclear maturation, and the expression of SHH-related proteins (PTCH1, SMO, and GLI1) in both the oocyte and its surrounding cumulus cells | Enhanced cleavage, blastocyst formation rates, and total cell number after PA | (Lee et al., 2018) |
Melatonin | Pig | Increased cumulus cell expansion and the expression of SHH-related proteins (PTCH1, SMO, and GLI1) in both the oocyte and its surrounding cumulus cells | Enhanced blastocyst formation rate and total cell number after PA | (Lee et al., 2017) |
ERK1/2, extracellular signal-regulated protein kinase 1/2; PTCH1, patched 1; SMO, smoothened; GLI1, glioma-associated oncogene homolog 1; PA, parthenogenetic activation; IVF,
The SHH signaling pathway can also be exploited as an indicator of oocyte quality. Previous reports have demonstrated that high-quality oocytes as assessed by brilliant cresyl blue (BCB) staining had greater potential to expand their surrounding cumulus cells along with reduced apoptosis and active SHH signaling (Lee et al., 2020). High-quality cumulus-oocyte complexes (COCs) in turn showed enhanced cumulus expansion, oocyte nuclear maturation, and preimplantation embryonic development. In addition, they exhibited elevated expression of SHH signaling proteins including SHH, PTCH1, and GLI1 (Lee et al., 2020). The above findings collectively suggest that active signaling via the SHH pathway may be indispensible for the generation and/or maintenance of appropriate oocyte maturation environment.
Well-known antioxidants, such as resveratrol and melatonin, are known to activate the SHH signaling pathway in COCs and consequently improve oocyte maturation and subsequent embryonic development (Table 1). Lee et al. reported that the effect of resveratrol on cumulus cell expansion, oocyte nuclear maturation, and subsequent embryonic development in pigs is mediated via the SHH signaling pathway (Lee et al., 2018). Furthermore, improvement of cumulus cell expansion and subsequent embryonic development by melatonin has also been reported to occur through activation of SHH signaling (Lee et al., 2017). Given the relationship between SHH signaling pathway and oocyte maturation, it may be a suitable target for improving current IVM culture systems.
Recent studies have demonstrated the involvement of the SHH signaling pathway, which exists in ovarian follicles, in oocyte maturation (Fig. 1). In addition, it was also demonstrated that high quality oocytes have a greater potential to expand their surrounding somatic cells with active SHH signaling. Additionally, antioxidants including resveratrol and melatonin, improve oocyte maturation through SHH signaling activation. Therefore, activation of the SHH signaling pathway may aid in the establishment of an optimized IVM culture system by closely mimicking the
None.
Conceptualization, S.L. and J.C.; investigation: S.L. and J.C.; writing - original draft preparation, S.L. and J.C.; writing - review & editing: S.L. and J.C.
This work was supported by the BK21 Four program and the Korea Evaluation Institute of Industrial Technology (KEIT; 20012411).
Not applicable.
Not applicable.
Not applicable.
Not applicable.
No potential conflict of interest relevant to this article was reported.
Journal of Animal Reproduction and Biotechnology 2021; 36(4): 183-188
Published online December 31, 2021 https://doi.org/10.12750/JARB.36.4.183
Copyright © The Korean Society of Animal Reproduction and Biotechnology.
Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea
Correspondence to:Jongki Cho
E-mail: cjki@cnu.ac.kr
In vitro maturation (IVM) of oocytes is the procedure where the immature oocytes are cultivated in a laboratory until they are mature. Since IVM oocytes generally have low developmental competence as compared to those matured in vivo, development of an optimal IVM culture system by fine-tuning culture conditions is crucial to maintain high quality. In-depth knowledge and a deep understanding of the in vivo physiology of oocyte maturation are pre-requisites to accomplish this. Within ovarian follicles, various signaling pathways that drive oocyte development and maturation regulate interaction between oocytes and surrounding somatic cells. This review discusses the sonic hedgehog (SHH) signaling pathway, which has been demonstrated to be intimately involved in folliculogenesis and oocyte maturation. Advances in elucidating the role of the SHH signaling pathway in oocyte maturation will aid attempts to improve the current inferior in vitro oocyte maturation system.
Keywords: in vitro oocyte maturation, ovarian follicle, sonic hedgehog signaling
Oocyte maturation is a physiological process that precedes and is essential for successful fertilization and subsequent embryonic development (Lonergan and Fair, 2016). This process is initiated a few days prior to ovulation and involves progressive changes in ovarian follicles. These include preantral to early antral transition (Palma et al., 2012) and eventual acquisition of competence to resume meiosis and fertilizability (Paulini et al., 2014). Oocyte maturation is characterized by both nuclear and cytoplasmic maturation. The former is a complicated process that includes the resumption of meiosis post luteinizing hormone (LH) surge or oocyte release from a follicle (Luciano and Sirard, 2018). Mammalian oocytes enter the early stages of meiosis during fetal life but remain arrested at prophase I until they become committed to ovulation in response to an LH surge (Grøndahl, 2008). Meiotic resumption induced by the LH surge is further stalled at metaphase II (Lonergan and Fair, 2016) which is then completed following fertilization (GGrøndahl, 2008). In contrast, cytoplasmic maturation is associated with organelle reorganization and storage of mRNAs, proteins, and transcription factors that are requisites for early embryonic development (Ferreira et al., 2009).
The functional unit of the ovary i.e. the ovarian follicle, consists of three types of cells: an oocyte, granulosa cells, and theca cells that provide an appropriate developmental environment for oocytes (Gougeon, 1996). Growing ovarian follicles demonstrate a bidirectional communication between the oocyte and surrounding somatic cells that is essential for appropriate proliferation and differentiation (Nilsson and Skinner, 2001). These communications are regulated by several classical signaling pathways, including the Wnt, insulin, Notch, and hedgehog (HH) pathways (Li et al., 2021). Wnt signaling pathway activation by Wnt2 and Wnt4 plays a crucial role in normal ovarian follicle development by promoting granulosa cell proliferation (Boyer et al., 2010; Wang et al., 2010). The insulin signaling pathway regulates follicle development in the later stages of oocyte growth and promotes oocyte development by either upregulating the binding efficacy of LH to receptors or the number of receptors itself (Das and Arur, 2017). The Notch signaling pathway is known to regulate granulosa cell proliferation, since treatment with a Notch signaling inhibitor resulted in a significant decreased in their number (Jing et al., 2017). Lastly, the HH signaling pathway has been postulated to be a target signaling pathway in ovarian follicle development, since expression of HH ligands at the primary follicle stage is well established (Wijgerde et al., 2005).
A comprehension of the signaling pathways involved in ovarian development will help design better strategies for the generation of higher quality IVM oocytes. This article discusses the sonic hedgehog (SHH) signaling pathway, which has been reported to be involved in folliculogenesis and oocyte maturation. We have further placed a special emphasis on the application of SHH-induced IVM systems owing to the widespread use of IVM oocytes both in research and in the production of genetically engineered animals via assisted reproductive technologies.
HH signaling was first discovered in
All components of the HH signaling pathway including the ligands (
The SHH signaling pathway is a complex signal transduction mechanism that controls precisely regulated developmental processes (Choudhry et al., 2014). Signal transduction via this pathway is initiated by the binding of SHH protein in an autocrine and/or paracrine fashion (Handrigan and Richman, 2010) and ultimately coordinates cell proliferation and differentiation in various cell types (Enomoto-Iwamoto et al., 2000; Osawa et al., 2006; Salda?a et al., 2016). However, the evidence that the SHH signaling pathway controls the development of ovarian follicles is of particular interest (Russell et al., 2007), since folliculogenesis and oocyte maturation proceed together until ovulation (Kidder and Vanderhyden, 2010). Several studies have demonstrated an association between SHH signaling pathway and oocyte maturation
Table 1. The role of sonic hedgehog (SHH) signaling pathway in
Supplement | Species | Effects | Preimplantation embryonic development | References |
---|---|---|---|---|
Recombinant SHH protein | Pig | Increased oocyte nuclear maturation, cyclin B1 content, ERK1/2 phosphorylation, and intracellular calcium release | Enhanced cleavage, blastocyst formation rates, and total cell number after PA | (Nguyen et al., 2009) |
Recombinant SHH protein | Goat | Increased oocyte nuclear maturation and ERK1/2 phosphorylation | Enhanced blastocyst formation rate and | (Wang et al., 2017) |
Resveratrol | Pig | Increased cumulus cell expansion, oocyte nuclear maturation, and the expression of SHH-related proteins (PTCH1, SMO, and GLI1) in both the oocyte and its surrounding cumulus cells | Enhanced cleavage, blastocyst formation rates, and total cell number after PA | (Lee et al., 2018) |
Melatonin | Pig | Increased cumulus cell expansion and the expression of SHH-related proteins (PTCH1, SMO, and GLI1) in both the oocyte and its surrounding cumulus cells | Enhanced blastocyst formation rate and total cell number after PA | (Lee et al., 2017) |
ERK1/2, extracellular signal-regulated protein kinase 1/2; PTCH1, patched 1; SMO, smoothened; GLI1, glioma-associated oncogene homolog 1; PA, parthenogenetic activation; IVF,
The SHH signaling pathway can also be exploited as an indicator of oocyte quality. Previous reports have demonstrated that high-quality oocytes as assessed by brilliant cresyl blue (BCB) staining had greater potential to expand their surrounding cumulus cells along with reduced apoptosis and active SHH signaling (Lee et al., 2020). High-quality cumulus-oocyte complexes (COCs) in turn showed enhanced cumulus expansion, oocyte nuclear maturation, and preimplantation embryonic development. In addition, they exhibited elevated expression of SHH signaling proteins including SHH, PTCH1, and GLI1 (Lee et al., 2020). The above findings collectively suggest that active signaling via the SHH pathway may be indispensible for the generation and/or maintenance of appropriate oocyte maturation environment.
Well-known antioxidants, such as resveratrol and melatonin, are known to activate the SHH signaling pathway in COCs and consequently improve oocyte maturation and subsequent embryonic development (Table 1). Lee et al. reported that the effect of resveratrol on cumulus cell expansion, oocyte nuclear maturation, and subsequent embryonic development in pigs is mediated via the SHH signaling pathway (Lee et al., 2018). Furthermore, improvement of cumulus cell expansion and subsequent embryonic development by melatonin has also been reported to occur through activation of SHH signaling (Lee et al., 2017). Given the relationship between SHH signaling pathway and oocyte maturation, it may be a suitable target for improving current IVM culture systems.
Recent studies have demonstrated the involvement of the SHH signaling pathway, which exists in ovarian follicles, in oocyte maturation (Fig. 1). In addition, it was also demonstrated that high quality oocytes have a greater potential to expand their surrounding somatic cells with active SHH signaling. Additionally, antioxidants including resveratrol and melatonin, improve oocyte maturation through SHH signaling activation. Therefore, activation of the SHH signaling pathway may aid in the establishment of an optimized IVM culture system by closely mimicking the
None.
Conceptualization, S.L. and J.C.; investigation: S.L. and J.C.; writing - original draft preparation, S.L. and J.C.; writing - review & editing: S.L. and J.C.
This work was supported by the BK21 Four program and the Korea Evaluation Institute of Industrial Technology (KEIT; 20012411).
Not applicable.
Not applicable.
Not applicable.
Not applicable.
No potential conflict of interest relevant to this article was reported.
Table 1 . The role of sonic hedgehog (SHH) signaling pathway in
Supplement | Species | Effects | Preimplantation embryonic development | References |
---|---|---|---|---|
Recombinant SHH protein | Pig | Increased oocyte nuclear maturation, cyclin B1 content, ERK1/2 phosphorylation, and intracellular calcium release | Enhanced cleavage, blastocyst formation rates, and total cell number after PA | (Nguyen et al., 2009) |
Recombinant SHH protein | Goat | Increased oocyte nuclear maturation and ERK1/2 phosphorylation | Enhanced blastocyst formation rate and | (Wang et al., 2017) |
Resveratrol | Pig | Increased cumulus cell expansion, oocyte nuclear maturation, and the expression of SHH-related proteins (PTCH1, SMO, and GLI1) in both the oocyte and its surrounding cumulus cells | Enhanced cleavage, blastocyst formation rates, and total cell number after PA | (Lee et al., 2018) |
Melatonin | Pig | Increased cumulus cell expansion and the expression of SHH-related proteins (PTCH1, SMO, and GLI1) in both the oocyte and its surrounding cumulus cells | Enhanced blastocyst formation rate and total cell number after PA | (Lee et al., 2017) |
ERK1/2, extracellular signal-regulated protein kinase 1/2; PTCH1, patched 1; SMO, smoothened; GLI1, glioma-associated oncogene homolog 1; PA, parthenogenetic activation; IVF,
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