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Human fertilization

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Human fertilization is the union of a human egg and sperm, . The result of this union is the production of a zygote, initiating prenatal development.

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Human fertilization

  1. 1. Maryam Borhani-Haghighi PhD student of Tehran Medical University
  2. 2. Maryam Borhani-Haghighi 11 Oocyte maturation  Nuclear maturation Cytoplasmic maturation
  3. 3. Maryam Borhani-Haghighi 12 Oocyte continues meiosis. Nuclear membrane of oocyte disappears. First polar body separates, and it enters the perivitelline space. Second meiotic division takes place and stops in the metaphase II. This process is known as the maturation of oocyte nucleus. Nuclear maturation
  4. 4. Maryam Borhani-Haghighi 13 Nuclear maturation Maturation Promoting Factor (MPF) activity during oocyte maturation. MPF activity appears just before germinal vesicle breakdown (GVBD). It falls down at the end of Meiosis I and reappears at the beginning of Meiosis II (MII). It remains high during MII-arrest of oocytes and decreases following fertilization..
  5. 5. Maryam Borhani-Haghighi 14 Cytoplasmic maturation Cytoplasmic maturation Organelle redistribution Mitochondria Endoplasmic reticulum (ER) Cortical granules lipid droplet Protein synthesis Cytoskeleton dynamics
  6. 6. Maryam Borhani-Haghighi 15 Mitochondria  Before the beginning of oocyte maturation. Homogenous distribution of mitochondria in the cell cortex is observed  After nuclear maturation, mitochondria are dispersed throughout the cytoplasm except the very central region of oocytes. BB - Balbiani body M - mitochondria n - nucleus
  7. 7. Maryam Borhani-Haghighi 16 Endoplasmic reticulum (ER)  ER :protein and lipid synthesis organelle  store of Ca2+ oocyte activation in during fertilization.  In mature oocytes, an accumulation of ER in the oocyte cortex, specifically in the region with cortical granule exocytosis and sperm-egg fusion
  8. 8. Maryam Borhani-Haghighi 17 Cortical Granule (CG)  Exocitosis of cortical granules plays an essential role in the block against polyspermy.  In immature oocytes, CGs are found in the whole cytoplasm (the cortex cytoplasm and the inner cytoplasm)  In mature oocytes, an asymmetric distribution of CGs in the cortex is observed.
  9. 9. Maryam Borhani-Haghighi 18 Lipid droplets (LD)  Energy supply necessary for meiotic, maturation, fertilization and early embryo development  In GV - stage oocytes, a homogenous distribution has been reported.  In mature oocytes, Lipid droplets contribute to the oocyte polarization by surrounding the MII spindle.
  10. 10. 20 Cytoskeleton dynamics  During the GV stage, microfilaments are distributed throughout the cytoplasm, and during GVBD they migrate toward the oocyte cortex. Maryam Borhani-Haghighi
  11. 11. Maryam Borhani-Haghighi
  12. 12. The sperm has to pass several barriers to enter the egg. 1.layer of cumulus cell. 2. zona pellucida Maryam Borhani-Haghighi
  13. 13. Maryam Borhani-Haghighi Zona pellucida
  14. 14. Maryam Borhani-Haghighi 33 The zona pellucida (plural zonae pellucidae, is a glycoprotein membrane surrounding the plasma membrane of an oocyte. Zona pellucida
  15. 15. Maryam Borhani-Haghighi 35 ZP3 mediates Sperm-Specific Egg Binding ZP2 mediates subsequent sperm binding ZP1 cross-links ZP2 and ZP3 as protein meshwork Zona pellucida
  16. 16. Maryam Borhani-Haghighi 40  As a receptor  Inducer of Acrosomal Reaction  Blockade of heterospecific fertilization. Species-specific barrier to sperm binding and penetration;  Prevention of polyspermy  Protection of the embryo before implantation Functions of the ZP include
  17. 17. • ZP keeps sperm of foreign species out .( Not 100% effective; some cross-species fertilization can occur (e.g., horse & donkey = mule; some speciesof monkeys can cross fertilize) ) • Remove the ZP and other species sperm can fertilize and egg (e.g., Hamster Test for Male Fertility; human sperm can fertilize the zona-less hamster egg) Maryam Borhani-Haghighi
  18. 18. • The mutant mice which lacked ZP3 couldn't bind the sperm to the zona pellucida and thus did not get fertilized • When their missing ZP3 gene was replaced with a human ZP3 gene, the mice made the human ZP3 and it was incorporated into their zona pellucida. With the human ZP3 in their zonas the eggs could be fertilized by mouse sperm revealing that human and mouse ZP3 can mediate the same critical events. Maryam Borhani-Haghighi
  19. 19. Maryam Borhani-Haghighi 34 Zona pellucida Inner zone Outer zone Birefringence
  20. 20. Maryam Borhani-Haghighi 37 (a): Outer surface of the ZP of a human mature oocyte. Many fenestrations are present in which the filaments form a large meshed network (b): Outer surface of the ZP of a human atretic oocyte. The filaments form a tight meshed network.
  21. 21. Maryam Borhani-Haghighi 38 (b): The ZP appears completely compact and with a smooth surface. (d): High magnification of (b) showing the compact and dense structure of the zona. Human atretic oocyte
  22. 22. Maryam Borhani-Haghighi 39 This metaphase II oocyte displays an atypical aspect of the ZP. Projections from the ZP give the oocyte a hairy, brush- like appearance. Abnormality of the zona pellucida
  23. 23. Maryam Borhani-Haghighi
  24. 24. Maryam Borhani-Haghighi Capacitation of sperm
  25. 25. 43 Capacitation of sperm Reduction in membrane cholesterol increase fludity Hyperactivaty of sperm ;lateral movement of head Removal of coating factors Only capacitated sperm can bind to the ZP Maryam Borhani-Haghighi
  26. 26. Maryam Borhani-Haghighi 52 Maturation-Ejaculation-Capacitation Leaving testis-Epididymis-seminal plasma-Oviduct
  27. 27. Maryam Borhani-Haghighi
  28. 28. 5 sets of molecular changes are considered important for capacitation: 1.Sperm membrane sheds cholesterol by albumin allowing for zona pellucida recognition 2.Protein/carbohydrate loss opens sperm-egg recognition sites 3.Membrane potential of the cell membrane become more negative activating cAMP production 4.Protein phosphorylation occurs forming a receptor 5.Acrosomal membrane changes Maryam Borhani-Haghighi
  29. 29. Maryam Borhani-Haghighi 45 Reduction In Membrane Cholesterol
  30. 30. Cholesterol efflux during the early phases of capacitation increases plasma membrane fluidity, facilitating the entry of bicarbonate (HCO3-) and calcium ions (Ca2+) into the sperm cytosol through specific membrane channels. Maryam Borhani-Haghighi
  31. 31. Maryam Borhani-Haghighi
  32. 32. Model of mammalian sperm capacitation soluble adenylyl cyclase (SACY) Maryam Borhani-Haghighi
  33. 33. which then simultaneously inhibits the activity of tyrosine phosphatases (PTP) and activates tyrosine kinases (PTK). cAMP, activate protein kinase A (PKA), leading to the production of the second messenger cyclic AMP (cAMP). soluble adenylyl cyclase (SACY) is activated by increases in intracellular bicarbonate, calcium and pH increase in protein tyrosine phosphorylation capacitation Maryam Borhani-Haghighi
  34. 34. • membrane remodeling events(Cholesterol ) redistribution of membrane rafts to the anterior region of the sperm head. • This event may serve to reposition key zona pellucida receptor molecules • membrane remodeling events may be augmented by the action of chaperones that are themselves activated during capacitation. Maryam Borhani-Haghighi
  35. 35. Maryam Borhani-Haghighi 50 EGF  Epidermal growth factor (EGF)interacts with its receptor tyrosine kinase (EGFR)  stimulates the tyrosine phosphorylation of several proteins enhances actin polymerization during capacitation
  36. 36. Maryam Borhani-Haghighi 54 Hyperactivaty of sperm  CatSper, sperm cation channel that is localized in a principal piece of the mature sperm tail.  gene knockouts that are CatSper have poorly motile sperm that completely fail to fertilize eggs
  37. 37. Maryam Borhani-Haghighi
  38. 38. Maryam Borhani-Haghighi 23 Role of actin cytoskeleton in mammalian sperm capacitation • In human sperm the regions reported to contain actin include the acrosomal space, the equatorial and post acrosomal regions, and the tail.  actin polymerization and depolymerization might be involved in sperm function.  actin polymerization occurs during capacitation  F-actin breakdown should occur in order to achieve the acrosome reaction. inhibition of actin depolymerization by phalloidin inhibits the reaction.
  39. 39. Maryam Borhani-Haghighi 3124
  40. 40. Maryam Borhani-Haghighi 31 Sperm penetration to corona radiata
  41. 41. Maryam Borhani-Haghighi 56  hyaluronic acid–rich layer of cumulus cells surrounds the ovulated oocyte. Sperm penetration to corona radiata
  42. 42. Maryam Borhani-Haghighi 31 Acrosomal reaction & penetration to zp
  43. 43. The Acrosome Reaction: • When sperm contacts the egg cell layers, the it has an intact acrosome. • stimulation of the sperm by agents from the corona radiata followed by binding to the zona pellucida, leads to the acrosome reaction Maryam Borhani-Haghighi
  44. 44. The Acrosome Reaction: Galactosyltransferase binding • Here we will look at only one of the classic mechanisms of sperm-egg binding that leads to the acrosome reaction: Galactosyltransferase binding that occurs at the zona pellucida. Maryam Borhani-Haghighi
  45. 45. Galactosyltransferase • Each sperm has galactosyltransferase (GalTase) enzymes on its head • Galactosyltransferase is an enzyme that transfers a sugar group from one molecule to another Maryam Borhani-Haghighi
  46. 46. Unlike normal enzyme reactions in which the enzyme binds its substrate and produces products, this enzyme reaction cannot go to completion. Since it can’t complete the reaction the enzyme and the substrate remain attached to each other. Maryam Borhani-Haghighi
  47. 47. • Each sperm binds N-acetylglucosamine, GlcNAc) residues in ZP3 via galactosyltransferase (GalTase) enzymes in the sperm cell membrane. Thus the GlcNAc is the substrate for the GalTase enzyme. • so the sperm remain attached via the sugar-enzyme binding because the enzyme reaction cannot go to completion . Maryam Borhani-Haghighi
  48. 48. ZP3 and the Acrosome Reaction Maryam Borhani-Haghighi
  49. 49. • As more GalTase enzymes bind more GlcNAc substrates the receptors on the sperm head cluster together • This clustering alters the sperm cell membrane causing calcium levels to increase in the sperm cytoplasm • The increase of intracellular calcium mediates the fusion of the acrosomal and sperm cell membranes • This allows the contents of the acrosome to flow out • The released Acrosomal enzymes now begin to digest a path for the sperm through the zona pellucida Maryam Borhani-Haghighi
  50. 50. Maryam Borhani-Haghighi
  51. 51. Calcium & the Acrosome Reaction Maryam Borhani-Haghighi
  52. 52. Maryam Borhani-Haghighi
  53. 53. In freshly ovulated eggs, ZP3 is in very close physical association with ZP2. Acrosome-reacted sperm bind to ZP2 via their exposed inner acrosomal membranes, penetrate the zona, fuse with the oocyte, and fertilize the egg. Maryam Borhani-Haghighi
  54. 54. Immediately after fertilization, cortical granules release a ZP2- specific protease and other enzymes into the perivitelline space. This cortical granule protease clips ZP2 and converts it into the cleaved form (ZP2c) that no longer supports the binding of acrosome-reacted sperm. ZP3 dissociates from ZP2c, and undergoes a subtle modification that converts it into a form (ZP3f) that lacks sperm receptor and acrosome- inducing activity. Maryam Borhani-Haghighi
  55. 55. Maryam Borhani-Haghighi
  56. 56. Maryam Borhani-Haghighi Hyaluronidase neuraminidase acrosin protease trypsin-like enzyme Arylsulfatase PLC Esterase
  57. 57. Maryam Borhani-Haghighi  Ca2+- Calcium is an important modulator for capacitation and AR and is probably the key messenger in the information exchange between sperm and egg .  Progestrone  Follicular fluid  Coffein  K+ and Na+ Acrosomal reaction
  58. 58. SOC Store-operated channels Progesterone cause Ca2+influx ::::::Elevation of Ca2+in the midpiece/proxim al flagellum ::::::leading to regulation of flagellar activity Maryam Borhani-Haghighi
  59. 59. What is progesterone? Progesterone is a steroid hormone made by both men and women. In women, it is made the corpus luteum of the ovary the adrenal glands. In men, is produced in adrenal testicular tissue.Maryam Borhani-Haghighi
  60. 60. Maryam Borhani-Haghighi 65 Result of Acrosomal Reaction Acrosomal bulb Ca / cAMP Ph (7.1 7.5) Zp Zp2f
  61. 61. Maryam Borhani-Haghighi 31 Sperm oolemma binding & fusion
  62. 62. Maryam Borhani-Haghighi 70 Sperm oolemma binding & fusion • The observation that acrosome intact sperm can bind to zona-free eggs, but do not fuse with them, suggests that membrane alterations occurring during the acrosome reaction are required for fusion.
  63. 63. Sperm Binding to the Zona & the Egg Cell Membrane • several proteins that mediate these membrane interactions, fertilin b. Mouse mutants that lack fertilin b have a markedly reduced fertility. Maryam Borhani-Haghighi
  64. 64. Maryam Borhani-Haghighi 70 The sperm plasma membrane • Fertilin α • Fertilin β • Cyritestin • ADAM 4 • ADAM 5 • IZUMO
  65. 65. molecules on the sperm surface, such as fertilin and cyritestin3, involved in sperm–egg binding Izumo is essential for membrane fusion On the egg, CD9 is required for fusion and might collaborate with other proteins such as integrins or glycosylphosphatidyl inositol (GPI)- anchored proteins Maryam Borhani-Haghighi
  66. 66. Maryam Borhani-Haghighi 70 • members of a new family of membrane proteins, the ADAM family (a disintegrin and metalloprotease disintegrin • cysteine-rich • EGF-like Fertilin • fertilin, a heterodimeric (α and β subunits) sperm membrane protein, is involved in the fusion process. • This protein is located on the posterior head of acrosome-reacted sperm.
  67. 67. Maryam Borhani-Haghighi 70 • Localization of cyritestin in the equatorial region is consistent with its participation in sperm–egg fusion. • Although both the equatorial regions and posterior head of the sperm membrane fuse with the egg membrane, cyritestin
  68. 68. Maryam Borhani-Haghighi 70 The Egg .CD9 .CD81 Glycosylphosphatidyl inositol (GPI)-anchored
  69. 69. Maryam Borhani-Haghighi 70 • immunofluorescence microcopy shows that CD9 is localized to the microvillar- rich region of the egg CD9
  70. 70. Maryam Borhani-Haghighi 70 CD81 • CD81, which fairly closely resembles CD9 in structure and some functions, has a role in gamete fusion. However, the results of deleting the CD81 gene are less dramatic than those seen with the deletion of CD9.
  71. 71. Maryam Borhani-Haghighi 70 Sperm oolema binding & fusion The egg plasma membrane can be divided into two major regions. 1.The part of the membrane that directly overlies the metaphase chromosomes has a smooth surface devoid of microvilli. 2. The remainder of the egg is rich in microvillar protrusions. This is the region of the egg where sperm both bind and fuse.
  72. 72. Maryam Borhani-Haghighi
  73. 73. Maryam Borhani-Haghighi 70 Fertilization cone
  74. 74. Block to Polyspermy • Special blocks to polyspermy exist: • 1. Fast Block: electrical change in egg membrane 2. Slow Block: modification of zona pellucida Maryam Borhani-Haghighi
  75. 75. Maryam Borhani-Haghighi 70
  76. 76. Maryam Borhani-Haghighi 70 Slow block to polyspermy • Elavation of Ca2+ • Cortical granule reaction Exocytosis Perivitteline space  Zp2  β-hexoaminidase  Tyrosin
  77. 77. Slow block of polyspermy The Cortical Reaction • Calcium not only plays a role in the acrosome reaction, it also mediates the subsequent event of corticalgranule exocytosis in the egg. • Ca2+ induces local exocytosis of cortical granules • Granules release to stimulate adjacent cortical granules to undergo exocytosis • Wave of exocytosis occurs around egg in 3 dimensions from original site of sperm entry Maryam Borhani-Haghighi
  78. 78. Maryam Borhani-Haghighi
  79. 79. Maryam Borhani-Haghighi
  80. 80. Maryam Borhani-Haghighi
  81. 81. Maryam Borhani-Haghighi
  82. 82. Maryam Borhani-Haghighi 70 Calcium signals at fertilization • A “Ca2+ wave” that starts from the site of sperm–egg fusion and propagates across the egg cytoplasm has been extensively analyzed
  83. 83. Fast block of polyspermy • is the electrical charge across the surface of the egg, which is caused by the fusion of the first sperm with the egg.  Elevation of intracellular PH  Change the membrane potential  Resting potential: -75 mV  Fertilization potential: +20 mV Maryam Borhani-Haghighi
  84. 84. Maryam Borhani-Haghighi a) Glutathione b) Heparin c) Zn Decondensation of sperm nucleus
  85. 85. From the following cell is seen the protamine to histone transition where maternally derived histones replace protamines resulting in the decondensation of the sperm headMaryam Borhani-Haghighi
  86. 86. Human sperm nuclear decondensation in vivo involves protamine disulfide bond reduction by glutathione (GSH) and protamine/histone exchange, presumably with heparan sulfate (HS) as the protamine acceptor Maryam Borhani-Haghighi
  87. 87. A significant fraction of the zinc is lost from sperm chromatin when the cysteine thiols in protamine are oxidized into disulfide bonds. Extraction of zinc from the freshly ejaculated spermatozoon allows immediate decondensation Maryam Borhani-Haghighi
  88. 88. • Male PN : 22.1 µm • Female PN : 24.4 µm • Male PN has more Nucleoli • Female PN is close to polar body The male pronucleus is colorized in blue; female in pink. Maryam Borhani-Haghighi
  89. 89. Maryam Borhani-Haghighi 70 Role of tail sperm-aster  A centrosome with astral rays in the cytoplasm of an inseminated ovum;  it is brought in by the penetrating spermatozoon and gives rise to the mitotic spindle of the first- cleavage division. Proximal centriol
  90. 90. Maryam Borhani-Haghighi 31 syngamy
  91. 91. Maryam Borhani-Haghighi 70 Syngamy Union of gametes resulting in formation of a zygote syngamy
  92. 92. Maryam Borhani-Haghighi 31 Singamy
  93. 93. At gamete fusion the sperm tail is incorporated into the ooplasm, the centriolar region forms the sperm aster while the sperm head is decondensing ; this aster acts to guide the female pronucleus towards the male pronucleus. The centriole duplicates during the pronuclear stage, and at syngamy centrioles are found at opposite poles of the first cleavage. The centrosome has several implications for human infertility. It is possible that immotile or nonprogressively motile spermatozoa may possess centriolar abnormalities or an absence of centrioles. Similarly, antisperm antibodies against centrioles may be responsible for mitotic arrest. One way of solving this problem would be the use of donor centrosomesMaryam Borhani-Haghighi
  94. 94. Maryam Borhani-Haghighi Pronuclear scoring system • 16-18 hours after fertilization • Grading is based on: – Pronuclear size, symmetry & position – Size, number, equality & distribution of nucleoli – Appearance of cytoplasm Van Blerkom (1990)
  95. 95. Maryam Borhani-Haghighi Pronuclear size & symmetry  Embryos containing tree or More PNs are polyploid:  injection of more than one sperm  sperm chromatin disperse  second polar body extrusion failure
  96. 96. Maryam Borhani-Haghighi What is cleavage? Cleavage is a rapid series of mitotic divisions that occur just after fertilization. There are two critical reasons why cleavage is so important: 1. Generation of a large number of cells that can undergo differentiation and gastrulation to form organs. 2. Increase in the nucleus / cytoplasmic ratio. Eggs need a lot of cytoplasm to support embryogenesis. It is difficult or impossible for one nucleus to support a huge cytoplasm, and oocytes are one of the largest cells that exist. One small nucleus just cannot transcribe enough RNA to meet the needs of the huge cytoplasm.
  97. 97. Maryam Borhani-Haghighi Cleavage differs from normal mitoses in 2 respects Normal eukaryotic cells divide slowly, once every several hours or days. The cell cycle has G1 and G2 periods. During G1 the cell synthesizes RNA and other components for cell growth. Cleavage consists of very rapid successive mitoses. Since the egg has stored large amounts of RNA and other material, it does not need G1 or G2. However, as the number of cells increases, the nucleus / cytoplasmic ratio also increases. The rate of cell division slows because the cell now needs to synthesize its own RNA and grow between divisions. Thus, G1 and G2 are restored
  98. 98. Maryam Borhani-Haghighi Asynchronous cleavage: mammalian embryos are unusual in that they have asynchronous cleavage. Not all blastomeres divide at the same time. The first cleavage is meridional, and the second cleavage is rotational. The 2 blastomeres divide in different planes (one is equatorial and one is meridional
  99. 99. Maryam Borhani-Haghighi Cleaved embryo assessment 24-28 hours after insemination 2 cells 40-44 hours after insemination 4 cells 64-68 hours after insemination 8 cells
  100. 100. Maryam Borhani-Haghighi •Morula stage in mammals begins when the embryo consist of 16 blastomers , occurs 3 to 4 days after fertilization, when embryo passes from oviduct into the uterus MORULA
  101. 101. Maryam Borhani-Haghighi Compaction During compaction each of the eight blastomeres undergo a polarization. Polarization and the formation of tight junction allow the blastomers to create an inner embryo environment that is different from the outside environment Tight junctions develop beneath ext. surfaces and gap junction form between the internal surfaces
  102. 102. Maryam Borhani-Haghighi Blastocyst Morphology • Thin zona pellucida. • Smooth trophoectoderm. • Equality & close adhesion of blastomeres. • Clearly visible blastocyst cavity. • Well developed inner cell mass. Blastocyst scoring is based on: blastocyst, Inner cell mass, trophectoderm
  103. 103. Maryam Borhani-Haghighi eomesoder min Cdx2 Trophobla st Oct4 Nanog ICM
  104. 104. Maryam Borhani-Haghighi 70 The act of hatching involves the local digestion of the zona by an enzyme produced in patch of trophoblast cells situated opposite the inner cell mass (this location minimizes the risk of collateral enzymatic damage to the embryo Having escape from the zona ,the blastocyst begins the process of implantation Hatching
  105. 105. Maryam Borhani-Haghighi Metabolic Shift • Maturing oocytes use more pyruvate than immature and non-transitional oocytes. • In the early stages of early development the embryo uses pyruvate switching to glucose. • The use of pyruvate, glucose and lactate production indicating embryo health.
  106. 106. Maryam Borhani-Haghighi • Blastocyst with a glucose uptake >5µg/h develop better in culture and give rise to more pregnancies. • Morphologically normal blastocyst use more glucose than degenerating blastocyst.
  107. 107. Thank you for your attention Thank you for your attentionMaryam Borhani-Haghighi
  108. 108. Maryam Borhani-Haghighi 70 Thank you for your attention
  109. 109. Developing Embryo Thank you for your attention Maryam Borhani-Haghighi
  110. 110. Maryam Borhani-Haghighi

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Human fertilization is the union of a human egg and sperm, . The result of this union is the production of a zygote, initiating prenatal development.


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