Trends in Molecular Medicine
ReviewCrosstalk between Sertoli and Germ Cells in Male Fertility
Section snippets
Biologically Active Biomolecules That Mediate Crosstalk Between Cells in the Seminiferous Epithelium
Through spermatogenesis, millions of sperm are produced on a daily basis. During spermatogenesis, cellular events pertinent to (i) self-renewal of undifferentiated spermatogonia via mitosis, (ii) the production of haploid spermatids via meiosis I/II, (iii) the differentiation of spermatids to spermatozoa via spermiogenesis, and (iv) the release of sperm at spermiation are supported by intricate crosstalk between Sertoli cells and between Sertoli and germ cells [1, 2, 3, 4, 5]. A single
F5-Peptide Modulates Cell Adhesive Function to Support Spermatogenesis
In the mammalian testis, the unique cell–cell AJ designated the ES is expressed at the Sertoli–spermatid (step-8–19 spermatids in rats) interface called the apical ES as well as at the Sertoli cell–cell interface designated the basal ES (Figure 1) [28,29]. The ES is typified by the presence of actin filament bundles that lay in parallel to the plasma membrane in Sertoli cells, sandwiched between the adjacent plasma membranes of the apposing Sertoli cell–elongated spermatid and the cisternae of
Mechanistic Insights into F5-Peptide/p-FAK-Y407 Signaling in BTB Remodeling
FAK was first reported to be a component of the ES in studies using a specific antibody that localized FAK near the basement membrane [37], at the base of the seminiferous epithelium, adjacent to Sertoli cells and undifferentiated spermatogonial cells and is the modified form of ECM in mammalian testes [38]. Subsequent studies have shown that p-FAK-Y397 is robustly expressed at the apical ES from late stage VII through late VIII until the release of sperm at spermiation, supporting the notion
NC1-Peptide: A New Regulatory Protein to Support Apical ES and Basal ES/BTB Function
Besides laminins [42, 43, 44], collagens are another major structural constituent of the basement membrane [45, 46, 47]. One of the major collagen chains in the basement membrane is the collagen α3 (IV) chain [42]. Each monomer of the type IV collagen is assembled from three α3 chains, creating a triple-helical structure [47] (Figure 3). Each chain has an N-terminal noncollagenous 7S domain comprising ∼15 amino acid residues, a long central collagenous domain of ∼1400 residues comprising
LG3/4/5-Peptide Supports Sertoli Cell TJ Barrier Function
The basement membrane in the testis comprises laminins, collagen (type IV) chains, nidogens, and heparan sulfate proteoglycans [38,42,64,65]. Functional laminins are heterotrimers of α-, β-, and γ-chains. To date, there are five α-, three β-, and three γ-chains, giving rise to at least 15 protein isoforms via different combinations that are found in different tissues [65,66] (Figure 4). The laminin-α1 and -α5 chains are involved in early embryonic development and/or organogenesis, while
The mTORC1/rpS6/Akt1/2 Signaling Complex in LG3/4/5-Peptide-Mediated Effects on Sertoli Cell TJ Barrier Function
Laminin-α2 knockdown in Sertoli cells by RNAi was found to display considerable upregulation of the expression of p-rpS6-S235/S236 and p-rpS6-S240/S244, with concomitant downregulation of p-Akt1-S473 and p-Akt2-S474 [20], implicating mTORC1/rpS6/Akt1/2 as the downstream signaling pathway utilized by LG3/4/5-peptide to modulate spermatogenic function, such as the BTB function (Figure 2). Earlier studies have shown that the mTORC1/rpS6 signaling complex modulates Sertoli cell BTB function through
Role of F5-, NC1-, and LG3/4/5-Peptides in Mediating Crosstalk to Support Spermatogenesis: A Hypothesis
As shown in Figure 1, we propose a model wherein the testis utilizes F5-, NC1-, and LG3/4/5-peptides to modulate spermatogenic functions through their differential effects on the BTB and spermatid adhesion across the seminiferous epithelium. For instance, the F5-peptide generated from the laminin-γ3 chain at the apical ES promotes BTB remodeling, such as of the ‘old’ BTB located above the preleptotene spermatocytes to support their transport across the barrier, but also potentiates degeneration
Clinical Potential
Recent studies in adult Sprague–Dawley rats have shown that F5-, NC1-, and LG3/4/5-peptides, and some of their downstream signaling proteins such as the mTORC1/rpS6 signaling complex and p-FAK-Tyr407 (Figure 2), could possibly be used to modify blood–tissue barrier function. The action of these peptides and/or biomolecules can in turn modify drug transport function at the BTB. In brief, if the permeability of the BTB can be transiently modified by one of these peptides, such as F5-peptide [18,19
Concluding Remarks
We have provided a hypothetical model by which these three bioactive peptides mediate crosstalk between Sertoli and germ cells to modulate junction remodeling to support spermatogenesis as noted in Figure 1. However, since these peptides exert their effects through changes in the cytoskeletal organization of F-actin and MTs across the seminiferous epithelium, it is likely that these bioactive peptides also modulate other cellular events pertinent to spermatogenesis, such as meiosis I and II,
Acknowledgments
This work was supported in part by grants from the National Institutes of Health (NICHD, R01 HD056034 to C.Y.C.), National Natural Science Foundation of China (81730042 to R.G.), and Science and Technology Department of Zhejiang Province (2019C03035 to R.G.).
Glossary
- Adherens junction (AJ)
- actin-based cell–cell anchoring junction in epithelia or endothelia, usually located behind an actin-based TJ. An AJ is usually created by adhesion protein complexes such as cadherin/catenin and nectin/afadin linked to the actin cytoskeleton.
- Blood–testis barrier (BTB)
- one of the tightest blood–tissue barriers that provides a transcellular and paracellular barrier by restricting the diffusion of water, electrolytes, macromolecules, and biomolecules across the Sertoli cell
References (118)
Regulation of spermatid polarity by the actin- and microtubule (MT)-based cytoskeletons
Semin. Cell Dev. Biol.
(2018)Biology and regulation of ectoplasmic specialization, an atypical adherens junction type, in the testis
Biochem. Biophys. Acta
(2008)- et al.
Laminin α3 forms a complex with β3 and γ3 chains that serves as the ligand for α6β1-integrin at the apical ectoplasmic specialization in adult rat testes
J. Biol. Chem.
(2006) Perfluorooctane sulfonate induces neuronal and oligodendrocytic differentiation in neural stem cells and alters the expression of PPARγ in vitro and in vivo
Toxicol. Appl. Pharmacol.
(2013)- et al.
Regulation of the immune system by laminins
Trends Immunol
(2017) - et al.
Type III collagen (COL3A1): gene and protein structure, tissue distribution, and associated diseases
Gene
(2019) The effect of nonenzymatic glucosylation on the binding of the main noncollagenous NC1 domain to type IV collagen
J. Biol. Chem.
(1988)The discoidin domain receptor tyrosine kinases are activated by collagen
Mol. Cell
(1997)Hydra cell aggregate development is blocked by selective fragments of fibronectin and type IV collagen
Dev. Biol.
(1994)What is the role of peptide fragments of collagen I and IV in health and disease?
Life Sci
(2019)
Coxsackie and adenovirus receptor (CAR) is a product of Sertoli and germ cells in rat testes which is localized at the Sertoli–Sertoli and Sertoli–germ cell interface
Exp. Cell Res.
The nature and biology of basement membranes
Matrix Biol.
Expression and biological role of laminin-1
Matrix Biol.
Laminin α1 chain corrects male infertility caused by absence of laminin α2 chain
Am. J. Pathol.
mTOR signaling in growth control and disease
Cell
Dual inhibition of mTORC1 and mTORC2 perturbs cytoskeletal organization and impairs endothelial cell elongation
Biochem. Biophys. Res. Commun.
Emerging role for mammalian target of rapamycin in male fertility
Trends Endocrinol. Metab.
AF-2364 [1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide] is a potential male contraceptive: a review of recent data
Contraception
F5-peptide enhances the efficacy of the non-hormonal male contraceptive adjudin
Contraception
mTORC1/rpS6 and spermatogenic function in the testis – insights from the adjudin model
Reprod. Toxicol.
Male contraceptive adjudin is a potential anti-cancer drug
Biochem. Pharmacol.
Adjudin attenuates lipopolysaccharide (LPS)- and ischemia-induced microglial activation
J. Neuroimmunol.
Spontaneous muscular dystrophy caused by a retrotransposal insertion in the mouse laminin α2 chain gene
Neuromuscul. Disord.
Laminin α2 chain-null mutant mice by targeted disruption of the Lama2 gene: a new model of merosin (laminin 2)-deficient congenital muscular dystrophy
FEBS Lett.
Cell junction dynamics in the testis: Sertoli–germ cell interactions and male contraceptive development
Physiol. Rev.
Sertoli–Sertoli and Sertoli–germ cell interactions and their significance in germ cell movement in the seminiferous epithelium during spermatogenesis
Endocr. Rev.
Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 1: background to spermatogenesis, spermatogonia, and spermatocytes
Microsc. Res. Tech.
Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 2: changes in spermatid organelles associated with development of spermatozoa
Microsc. Res. Tech.
The cytology of the testis
Novel stage classification of human spermatogenesis based on acrosome development
Biol. Reprod.
Spermatogenesis and cycle of the seminiferous epithelium
Adv. Exp. Med. Biol.
Germ cell transport across the seminiferous epithelium during spermatogenesis
Physiology
A revised model for spermatogonial expansion in man: lessons from non-human primates
Reproduction
Spermatogonial stem cells: questions, models and perspectives
Hum. Reprod. Update
Sertoli–Sertoli and Sertoli–germ cell communications
Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 5: intercellular junctions and contacts between germ cells and Sertoli cells and their regulatory interactions, testicular cholesterol, and genes/proteins associated with more than one germ cell generation
Microsc. Res. Tech.
Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 4: intercellular bridges, mitochondria, nuclear envelope, apoptosis, ubiquitination, membrane/voltage-gated channels, methylation/acetylation, and transcription factors
Microsc. Res. Tech.
Physiological and physiopathological aspects of connexins and communicating gap junctions in spermatogenesis
Philos. Trans. R. Soc. Lond. B Biol. Sci.
Cross-talk between tight and anchoring junctions – lesson from the testis
Adv. Exp. Med. Biol.
A local autocrine axis in the testes that regulates spermatogenesis
Nat. Rev. Endocrinol.
A peptide derived from laminin-γ3 reversibly impairs spermatogenesis in rats
Nat. Commun.
F5-peptide induces aspermatogenesis by disrupting organization of actin- and microtubule-based cytoskeletons in the testis
Oncotarget
Basement membrane laminin α2 regulation of BTB dynamics via its effects on F-actin and microtubule (MT) cytoskeletons is mediated through mTORC1 signaling
Endocrinology
Regulation of the blood–testis barrier by a local axis in the testis: role of laminin α2 in the basement membrane
FASEB J
Focal adhesion kinase-Tyr407 and -Tyr397 exhibit antagonistic effects on blood–testis barrier dynamics in the rat
Proc. Natl Acad. Sci. U. S. A.
Perfluorooctanesulfonate (PFOS) perturbs male rat Sertoli cell blood–testis barrier function by affecting F-actin organization via p-FAK-Tyr407 – an in vitro study
Endocrinology
Rescue of PFOS-induced human Sertoli cell injury by overexpressing a p-FAK-Y407E phosphomimetic mutant
Sci. Rep.
Regulation of spermatogenesis by paracine/autocrine testicular factors
Asian J. Androl.
50 years of spermatogenesis: Sertoli cells and their interactions with germ cells
Biol. Reprod.
The Sertoli–germ cell communication network in mammals
Int. Rev. Cytol.
Cited by (99)
The role of Sertoli cells-secreted factors in different stages of germ cells development in mice exposed to BDE-209
2024, Environmental PollutionCross-talk between Vimentin and autophagy regulates blood-testis barrier disruption induced by cadmium
2024, Environmental PollutionCadmium exposure induces pyroptosis of TM4 cells through oxidative stress damage and inflammasome activation
2024, Ecotoxicology and Environmental Safety
- 4
These authors contributed equally