The Sertoli Cell Junction Dynamics
Falana, Benedict Abiola Department of Anatomy,
CMUL. Matriculation Number: 109091016
ANA 902
25th February 2014
1
OUTLINE
• INTRODUCTION• LITERATURE REVIEW• DISCUSSION–Sertoli cell structure–Sertoli cell function–Sertoli cell JUNCTIONS
• CONCLUSION• REFERENCES
2
INTRODUCTION: List of Abbreviations
BM= Basement Membrane ECM= Extracellular Matrix BTB= Blood-Testis Barrier TJs= Tight Junctions ES= Ectoplasmic
Specializations NAMPC= Nectin-Afadin
Multi Protein Complex ILMPC=Integrin-Laminin
Multi Protein Complex TT= Testosterone FSH= Follicle Stimulating
Hormone GDNF= Glial cell line
Derived Neutrotrophic Factor
CCMPC= Cadherin-Catenin Multiprotein Complex
IPEC-J2= Intestinal Epithelial cells
CAM= Cell dhesion Molecule
AC= Adenylate Cyclase MDCK= Mardin Darby Canine
Kidney CLASP= Cytoplasmic Linker
Associated Protein PI-3= Phosphatydyl Inosotol PLA2=Phospholipase A2, cAMP=Cyclic Adenosine
Monophosphate RHOB= Ras Homolgue B PKA= Protein Kinase A MAP Kinase= Mitogen Activated
Protein Kinase FGF- Fibroblast Growth Factor ICAM= Intercellular Adhesion
Molecule ST- Seminiferous Tubule FAK- Focal Adhesion kinase
NOS= Nitic Oxide Synthase CATNB= Beta Catenin B GJ= Gap Junction AJ= Adherens Junction AnJ= Anchoring Junctions CAM I = Calmodulin I NR5A1= Nuclear receptor
steroidogenic factor RAI 14- Retinoic acid
inducible protein 14 ZO- Zona Occludens CX43- Connexin 43 SRY- Sperm Region Y
TRAF4=TNF receptor associated factor
TM3= Transmembrane Segment 3 ILK= Integrin Linked Kinase ERM= Ezrin Radixin & Moesin GDNF=Glial Cell Line Derived
Neurotrophic Factor MIS=Mullerian inhibitory Substance JAM= Junction Adhesion Molecule TGFβ= Transforming Growth Factor
Beta ERK= Extracellular signal Regulated
Kinases ECL2= Extracellular loop 2 TNF= Tumor zNecrotic Factor SOX= SRY-related HMG Box GATA=Globin Transcription Factor
Introduction: SPERMATOGENESIS• 1. Spermatogonia– Proliferate by mitotic divisions
to provide stem cells & cells which will proceed through spermatogenesis (1º spermatocytes)
• 2. Spermatocyte– diploid cells (2n) give rise to haploid
cells (1n)
– 1º spermatocytes enter Meiosis I to form 2º spermatocytes which then enter Meiosis II and result in spermatids
• 3. Spermatids– spermatid differentiation into
spermatazoa 5
INTRODUCTION
Enrico Sertoli (University of Pavia Italy 1865)
1862; discovered Sertoli cell
Published in 1865
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Enrico Sertoli (1842 – 1910)
Questions• What is the mechanism of by which
developing germ cell traverse the epithelium?
• What signalling event determine the time of for germ cell to translocate from one site to the other?
• What interactions between Sertoli and germ cells take place during translocation?
• What are the events leading to formation and disruption of Sertoli-germ cell junctions?
Ultrastructure of the Sertoli Cell: Irregular nuceli, Mitochondria, lipid and RER are prominent.Courtesy : www.naturescience.com
• Ultrastructure of the Sertoli Cell: Irregular nuceli, Mitochondria, lipid and RER are prominent
LITERATURE REVIEW
On going Controversies.
• A Single Spermatogoonium (2n) gives rise to Eight Spermatids (1n)
(de Krester & Kerr 1988).
• Preleptotene and Leptotene spermatocytes. (Zipper Theory)
• BTB. (Byers 1993; Pelletier 2001).
• Sertoli-Germ cell bi-directional secretion of Androgen-binding protein. (Gunsalus & Bardin 1980).
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Table 2: Proteins Secreted by Sertoli Cells
• a Table modified from Griswold, 1988.
Hormones or Growth FactorsTGF- precursorAnti-Muillerian hormone (MIS)InhibinTGF-EGF-like growth factorBasic FGF-like growth factorSeminiferous growth factorIGF-1Interleukin-l-like factorLeydig cell stimulatory factor Basement Membrane ComponentsType IV collagenLaminin
EnzymesProcathepsin L (cyclic protein 2)Plasminogen activator Transport proteinsAndrogen-binding proteinTransferrinCeruloplasmin OtherSulfated glycoprotein 1 (prosaposin)Sulfated glycoprotein 2 (clusterin)TestibuminTestins
TABLE 1: Germ Cell-Sertoli Cell
Effects on Germ Cells Effects on Sertoli Cells
Limited differentiation in co-cultures
DNA and RNA synthesis
Protein synthesis
Viability and ATP levels
Adenylate cyclase activity
Protein phosphorylation
Alterations in glycoprotein composition
Alterations in membrane proteins
Transferrin secretion
ABP secretion
Estradiol secretion
Cyclic variations in secretory products
Reglation of Spermatogenesis
FSH.LH.TT.ABP.
(McLachlan et al., 2002 ; Kerr et al. 2006; ).
SRYSOX HMGFGF GATAFOGGADD 45gNRSA1 (Hiramatsu 2010; Pask 2010; Bormann 2011;
Johnen 2013)
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• CX43 alters Occludin expression in the rat ST.
(Gerber 2014)
• Spectrin and Plectin sorrounds the actin cuffs of apical tubulolobular complexes in the rat.
(Aristaeuss de Asis 2013)
• Clathrin/actin-base endocytic machinery is associated with junction turnover in ST.
(Vogl 2014).
• Dicer is required for sertoli cell function and survival.
(Papaioannou 2009; Kim 2010;Hensley et al., 2014).
16
• RIA 14 regulates F-actin dynamics at the ES.
(Qian 2013).
• CAM-I enhances Germ-Sertoli cell interaction in spermatogenesis.
(Lewis 2005; Wakayama & Iseki 2009)
17
• FAK is a regulator of F-actin dynamics (Li 2013)
• Disruption of Sertoli-germ cell adhesion function limited to adherens junctions.
(Xia et al., 2005)
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• Taurine disrupts the morphology and Ultrastructure in the testis of mice.
(Abdel-Moneim 2013)
• TGF-beta3 regulates anchoring junction dynamics via the Ras/ERK signaling pathway.
(Xia 2005)
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• Ultrastructural changes of the Sertoli and Leydig Cells following STZ induced diabetes.
~ Body Weight ↓ (P˂0.05)
~ Testicular Weight↓(P˂0.05) in diabetic rats compared with controls.
(Kianifard 2012)
• Β- Conglycinin reduces the tight junction occludin and ZO-I expression in IPEC-J2.
(Brosnan 2012 ; Zhao et al., 2014)
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• Palmitoy-protein thioesterase I
(PPTI) an obesity induced testicular
marker of reduced fertility. (Liu 2014)
• Claudin-3 and Claudin-5 folding and assembly into tight junctions are controlled by non- conserved residues in TM3 and ECL2 segments. (Rossa et al., 2014; Shabazi 2014).
23
• Immunohistochemical analysis of Histone H3 modifications in germ cells during mouse spermatogenesis.
(Song et al., 2011).
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• TRAF4 impedes the formation of tight junction integrin-linked kinase (ILK) Talin-1.
(Rosseau et al., 2014).
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DISCUSSION
STRUCTURE Blood-testis barrierControls the entry and exit of
nutrients hormones and other chemicals into the tubules
Makes the ad luminal part of ST, an immune privileged site.
(Wakayama 2009; Kopera 2010)
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SECRETION:
MIS
Inhibin
Activin
ABP
Estradiol aromatase. 27
GDNFERMTransferrin
(Xiong et al., 2006)
28
Hormones,Growth factors,Proteases (Catepsins,Metzincin,Plasminogens) Protease inhibitorsComponents of the extracellular matrix
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Junctions
The BTB
Tight junctions(TJs) Ectoplasmic specializations (BES)Tubulolobular complex (BTC) Desmosome-like junctions Hemidesmosomes
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Blood Testis Barrier- endocrine reviews
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BTB
FUNCTIONSAllow sertoli cells to control the
ad- luminal compartment.Regulates the chemical
composition of luminal fluid.Sensitive to trauma and Autoimmune response
32
TJs
COMPOSITION:
Fused membranesBead-like ComponentsSpan adjacent membraneFormed by strands of
transmembrane proteins .
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TJs
FUNCTIONS
Barrier FunctionImpermeableRegulates absorptionCreates a seal
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AJs
• Zona adherens
• Located at site of cell-cell interaction
• Actin-linked
• Attaches ECM
• Posses specific transmembrane receptors of the integrin family
• Adhesive function
Cadherin
Ca ion dependent CAMadhesion at adherens junction
Role:Teetheres cells to the ECM.Tranduce signals.Proliferation. Migration . Differentiation .
AnJ
• Desmosome-like junctions
• Ectoplasmic specializations
Key• 1.Peritubular cells
2. Basal membrane3.Spermatogonia4. Tight junction5. Spermatocyte16. Spermatocyte27a. spermatid7b. Spermatid8. Acrosome9. residual bodies10.Sperm cells11. Nucleus of sertoli cellA. Basal zoneB. Adlumunal zone
• www.instantanatomy.com.39
Desmosome-like Junctions
COMPOSITION
Macula adherensFound between Sertoli cells at the
BTBGerm cells up to but not including
step 8 spermatids. (Holthofer et al.,2007).
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Desmosome-like junctions
• COMPOSITION
Desmoglea. Dense Cytoplasmic plaques.
(Garrod et al., 2005; Holthofer et al., 2007; Scothern & Garrod 2008)
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Desmosome-like junctions
COMPOSITION: Cadherin family (a) Desmogleins (Dsg) (b) Desmocolins (Dsc) © IntegrinsAssociated with keratin & VinculinDistinct at molecular levelCalcium ion dependent (CAM)Sites of signal transduction
(Bruce et al., 2000)
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Desmosome-like Junctions
• FUNCTIONS~Mediate cell adhesion ( Delva et al.. 2007)
43
Desmosome-like junctions
FUNCTIONS: Cell adhesion Cell proliferation, Cell differentiation, Cell migration and Morphogenesis.
(Garrod & Chidley 2004)
44
ES
CCMPC
CATENIN ( α-β-ϒ-) :Cytoplasmic proteins Bind to the C-terminus of the type I/II and
desmosomal cadherins Regulates cadherin-mediated adhesion via
the actin and intermediate filament cytoskeletons
( Das et al., 2014)
45
ES
CCMPC (Wine & Capin 1999;Johnson & Boekelheide 2002; Lee et al., 2003, 2004; Yan et
al., 2008a; Delva & Kowalczyk 2009; Yan et al., ; 2008b; Izumi et al., 2006).
• Best studied actin-based adhesion unit.
46
Regulates:Cytoskeleton Cell polarity,Control of cell division andTumor suppression
• ( 5 distinct subfamilies, type 1 and 2, desmosomal, atypical, and cadherin-like)
47
ES
NAMPC
Nectins (1-5) Nectin-like molecules ( Necls,
Necls1-5)
--Ca++-independent
--immunoglobulin-like moles.
48
ES
Role:Adhesion ProliferationDifferentiationSurvivalMigrationCell polarity.( Takai & Natkanishi 2003; Takai et al., 2003, 2008c; Irie et al., 2004)
49
ES
ILMPC
Functions
• Connects a cell to ECM (Margadant et al., 2008; Geiger et al., 2009)
• Constituents of the BM (Miner & Yurchenco 2004; Miner 2008)
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SUMMARY
• The integrity of the BTB cannot be compromised.
• TJ on and off switch
• Signal transduction is very essential and crucial in tight junctional dynamics.
52
CONCLUSION
• Changes in secretory activity of either Sertoli or germ cells initially take place at the level of cell junctions.
• Biology of desmosome-like junctions and ES needs to be thoroughly investigated.
• Basis of male contraception and infertility treatment.
53
Acknowledgement
• Sincere gratitude to my able supervisors
Dr. Francis Duru and Dr. Abraham Osinubi for their mentorship role.
• I also want to appreciate my Teachers Dr. Ibeabuchi, Dr. Oremosu, Dr. Kusemiju, Dr. Dosumu, Dr. Olabiyi, Dr. Gbotolorun , Dr. Yama for their assistance during preparation for the review.
• A big thanks to fellow Postgraduate students and the non-teaching staff of the Department.
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