8 Development 1+2

• begin with gametogenesis (how eggs & sperm are formed)
• after discussing ovulation, we discuss fertilization: ‘the eureka day’
• then there are 17 days before gastrulation occurs
• gastrulation = ‘the most important 1-3 days of your life’; when the 3 germ layers form
• after gastrulation development starts occurring quite rapidly
• sometime during week 6 of prenatal development you can tell that an embryo is human (still only 0.5 inches long from crown to rump); but rudimentary structures are starting to form
• ‘embryonic period’ ends @ week 8
• 8 weeks & under = embryo; after 8 weeks = fetus
• as a fetus, all basic tissues have differentiated
• after 8 weeks, doing further differentiation + a lot of growth

• Embryologists: 38 weeks
• OG/GYNs: 40 weeks
• the actual time from conception to birth = 38 weeks
• however you don’t know the moment of conception/fertilization
• you DO know a woman’s last missed period - that’s why you add the 2 weeks, because it’s roughly 17 days from last missed period to when fertilization occurs

• includes both the embryonic period (weeks1-8)
• & the prenatal period (weeks 9-38)

the study of abnormal development (includes Birth defects, Anomalies, Congenital malformations)

by correlating the specific birth defect with the time the woman was taking thalidomide or contracted Rubella, scientists were able to figure out the timing events of critical structures in development

• specialized germ cells from the male & female
• are haploid as a result of meiosis

• formation of fully-developed gametes
• this begins much earlier than meiosis, even before the time of gonad differentiation during embryonic development
• in males this starts (& is essentially complete) in puberty - new sperm can be made every ~3 days
• in females it starts before birth & ENDS at fertilization (women don’t have complete gametes UNLESS they’re fertilized)

• how all somatic cells are produced (all cells in the body EXCEPT for the gametes)
• consists of only 1 round of DNA synthesis (S phase)
• always results in genetically identical diploid progeny cells

• end up creating very different progeny cells because meiosis starts with a round of S phase to create 4n (2 copies of each of the 2 chromosomes)
• then cell undergoes 2 successive rounds of cell division without any further replication of DNA
• produces only gametes
• sperm truly give rise to 4 gametes (each containing 1 chromosome)
• eggs only give rise to 1 gamete in reality (if fertilized, + polar bodies, vestigial, useless structures)

• only produces gametes
• consists of 1 round of DNA synthesis as in mitosis, acomplex interphase with genetic recombination, followed by 2 successive chromosome & cell divisions (Meiosis I & II) without an S phase
• the parent cell is diploid
• the progeny cells are haploid
• THE PARENT & PROGENY CELLS ARE GENETICALLY VERY DIFFERENT

• 4 months before birth (5th month of gestation) women have all the oocytes they’re ever going to have: ~ 7 million
• by the time females are born they’re already down to only a couple million
• eggs are designed to be perfect, & there’s still a selection process, but not like sperm, where it’s 1 out of a billion is chosen

• In females there are unequal meiotic divisions that produce a primary oocyte & a small polar body → then another unequal meiotoc division that produces a secondary oocyte & a second small polar body
• In males, meiotic divisions are all equal & all meiotic derivatives produce spermatids

• site of vasectomy is in the vas deferens
• sperm maturation is ~ a 3 day process
• takes place along the vas deferens - released when mature & can travel into epididymus

once the haploid gamete has developed, the:

• 1. golgi morphs into the Acrosome: a specialized golgi-derived structure found in the sperm head that’s filled with enzymes that help penetrate the egg
• 2. the nucleus exchanges histones for spermatadines, which pack DNA even tighter than histones
• 3. the mitochondria all move to one end of the cell where they form the mid-piece (between sperm head & tail) to provide energy for the tail (flagellum - axoneme, microtubule-based structure)

• primary (diploid) oocyte has to go from being a progenitor diploid cell through 2 rounds of meiosis to produce 1 mature (haploid) oocyte
• gives off 2 non-functional polar bodies
• 

• Hypothalamus-Pituitary-Ovary axis
• called HPT in males (T for testes)
• 

• the hypothalamus (brain) releases GnRH
• GnRH acts on the anterior pituitary, causing the synthesis & secretion of LH & FSH (the gonadotropins)

• released from the anterior pituitary & targets the ovary
• FSH stimulates ovarian follicle growth, differentiation, & steroidogenesis
• specifically, it stimulates 4-12 primordial follicles to grow, differentiate, & secrete estrogen + other steroid hormones

• released from the anterior pituitary & targets the ovary
• LH stimulates ovulation, corpus luteum formation, & steroidogenesis, especially progesterone

• released from ovarian follicle cells & act on the uterus, vagina, oviduct, & mammary glands
• crucial for the development of the uterus (& embryo if there’s a pregnancy)
• has negative feedback effects on the hypothalamus/GnRH release

• released from the corpus luteum & act on the uterus, vagina, oviduct, & mammary glands
• responsible for growth & differentiation of targets
• has negative feedback effects on the hypothalamus/GnRH release

1. Menstrual Phase: days 1-5

• 2. Follicular/Proliferative Phase: days 5-14
• secretion of FSH causes Estrogen levels to rise, which helps ovarian follicle maturation (& stimulates the re-growth of the uterine endometrium functional layer)
• the end of the follicular phase = LH surge (after enough FSH has been made)
• LH is required for ovulation (including that last bit of follicle maturation)
• ovulation usually occurs 12-18 hours after LH surge

• 3. Luteal/Secretory Phase: days 14-27
• estrogen levels peak then drop (not all the way though)
• progesterone levels are rising & high
• if no fertilization occurs, corpus luteum degenerates, estrogen & progesterone levels fall, & the secretory endometrium enters the ischemic phase

• 4. Ischemic Phase: days 27-28
• progesterone & estrogen levels fall rapidly & the functional endometrium becomes ischemic

going from a primary oocyte in a primordial follicle → primary oocyte in a primary follicle → secondary oocyte in a secondary follicle → finally a mature Graafian follicle

• disorganized structures in the ovary that exist predominantly in large numbers at 20 weeks (5 months) of gestation (can be found in adult women)
• consists of the oocyte + surrounding unorganized group of cells (no real made zona pellucida yet)
• the oocyte in a primordial follicle is always called a Primary Oocyte (primary means the oocyte is in meiosis I)

• what the primordial follicle develops into
• as the primordial follicle starts to develop, a zona pellucida will be formed
• oocyte surrounded by 2 or more layers of granulosa/follicular cells (epithelial cells that nourish & protect the oocyte)
• also thecal cells surround granulosa cells
• if an oocyte is in a primary follicle, it’s still a Primary Oocyte

• smooth muscle-like cells that contract very forcefully to expel the oocyte + surrounding follicular granulosa cells during ovulation
• also produce a lot of hormones + nutrients for the oocyte & protect it

• formed as the follicle matures (means cave)
• pushes the oocyte to one side of the follicle
• will fill up with follicular fluid, which is a substance very rich in nutrients/hormones that will help the surrounding cells proliferate & oocyte develop into a mature follicle

• type of granulosa/follicular cell that form a layer of cells just outside the zona pellucida & are an important source of nutrients for the oocyte
• they have lots of cytoplasmic ridges which directly connect them to the oocyte

• at the beginning of menstrual cycle, GnRH is made by
• hypothalamus
• this causes the anterior pituitary to release FSH into the bloodstream
• FSH stimulates 4-12 primary follicles to grow & secrete estrogen
• the follicle with the most FSH receptors on its supporting cells (granulosa + theca interna) will be the fastest growing, & therefore will become the dominant follicle
• the dominant follicle continues to mature & is ultimately ovulated
• it takes 2-3 menstrual cycles to complete ovulation of a particular follicle (it’s an ongoing process)
• the remaining developing follicles degenerate via apoptosis
• 8-10 follicles are lost during every cycle

• occurs when FSH-driven Estrogen levels rise to a certain threshold, rapidly stimulating LH production from the pituitary
• this LH surge is the trigger for ovulation & release of the primary oocyte from Prophase of Meiosis I
• the primary oocyte finishes Meiosis I, releases the first polar body, enters Meiosis II, where it arrests in Metaphase (II)
• the MOMENT an oocyte arrests in metaphase II it becomes a secondary oocyte, aka mature Graafian follicle
• the secondary follicle has a very large antrum
• the follicle ruptures & the secondary oocyte is expelled by contraction of the smooth muscle-like theca cells
• prostaglandins trigger the contractions
• the ovulated secondary oocyte is surrounded by the zona pellucida & one or more layers of follicular/granulosa/cumulus cells called the corona radiata
• ovulation occurs 12-24 hours after the LH surge

can either be caused by a translocation (+21 on another chromosome) or non-disjunction (trisomy 21)

• can occur because of a translocation
• Developmental delay, functionally severe
• Speech impairment, none or minimal use of words
• Movement or balance disorder
• Behavioral uniqueness: any combination of frequent laughter or smiling; apparent happy demeanor; easily excitable personality, often with hand flapping movements; short attention span
• Delayed growth in head circumference, usually resulting in microcephaly by age 2
• Seizures, onset usually<3 years of age

• another Chromosome 15 deletion
• can also occur because of a translocation?
• developmental delay
• poor muscle tone
• short stature
• small hands and feet
• incomplete sexual development
• unique facial features
• insatiable appetite

• major risk factor for infertility, birth defects
• up to age 35, the chance of having a child with a birth defect = 1/192 (~0.5%)
• post 35 there’s a fairly rapid increase in birth defect rate

• really rapid decline of primary oocytes - occurs via apoptosis
• causes a great majority of oocytes to go away
• by the time a woman hits puberty, she’s down to a few hundred thousand primary oocytes, compared to ~1 million at birth & ~6-7 million during gestation
• <0.01% of oocytes are ovulated
• this is likely not a random process: the less viable primary oocytes are likely the ones going through apoptosis

accelerated oocyte atresia

• sperm swim up the cervical canal using their flagella & are drawn up through the uterus + fallopian tubes by muscular contractions/ciliary movements
• sperm do 1/3rd of the work, the oocyte does 2/3rds - it takes a huge amount of energy for sperm to swim, but the female is doing most of the work
• FERTILIZATION occurs in the AMPULLA OF THE FALLOPIAN (uterine) tube
• fertilization can occur elsewhere in the Fallopian tube, but it does NOT occur in the uterus

• fertilization BEGINS with contact between sperm & secondary oocyte plasma membrane (“Eureka Moment”)
• it ends with intermingling of maternal & paternal chromosomes at metaphase of the first zygotic division ~24 hours later (the end of the “Eureka Day”)
• fertilization is a short process when compared to ovulation

• develops from ovarian follicle during the luteal phase of the menstrual cycle after a secondary oocyte from the follicle is released during ovulation
• it’s involved in the production of Progesterone when stimulated by LH
• if a pregnancy occurs, there is a Corpus Luteum of pregnancy that will be making ALL the progesterone for the embryo & fetus for the first 20 weeks
• Progesterone Insufficiency is the 3rd leading cause of SAB

• a hormone made by the implanted blastocyst (embryo) that PREVENTS the degeneration of the Corpus Luteum (for 20 weeks)
• after 20 weeks of gestation, the placenta makes enough estrogen & progesterone for the pregnancy

• if there’s no fertilization, the Corpus Luteum degenerates at the start of menses into the Corpus Albicans
• this is a regressed form of the Corpus Luteum that may persist as a scar on the surface of the ovary

• sperm concentration is normally 100 million sperm/mL of ejaculate
• the volume of each ejaculate is ~2-6 mL, meaning there are 200-600 million sperm in each ejaculate
• counts lower than 10 million/mL are associated with INFERTILITY
• prostaglandins in the semen stimulate muscular contractions in the female reproductive tract

• 1. Sperm Capacitation
• 2. Acrosome Reaction
• 3. ‘Eureka Moment’ (oozyte & sperm PMs fuse)
• 4. Cortical Reaction + Block to Polyspermy

• capacitation is necessary to give the sperm the capacity to move
• when they first enter the vaginal canal, they’re coated with glycoproteins & seminal proteins that have to be washed off their acrosome surface
• their protein coat has to be removed to give them the capacity to start swimming - takes 6-8 hours
• capacitated sperm are MORE ACTIVE & can undergo the acrosome reaction
• this step typically occurs in the female reproductive tract after ejaculation

• starts when contact is FIRST made between sperm & corona radiata (cumulus/follicular/granulosa cells), & is accelerated when sperm get to the zona pellucida
• when sperm contact the corona radiata cells, the acrosome membrane perforates due to the action of angiotensin converting enzyme (ACE) from the acrosome
• this causes release of enzymes that break down the matrix & permit sperm penetration through the follicular cells & the zona pellucida

• a zona pellucida glycoprotein
• sperm have ZP3 receptors that when activated are the primary inducer of the acrosome reaction
• the specificity of the ZP3 receptor is so tight that it won’t recognize another species’ ZP3 glycoprotein

• enzyme derived from the acrosome that perforates the sperm's own acrosome membrane
• this perforation releases enzymes that break down the matrix & allow the sperm to penetrate through the follicle & zona pellucida

• plasma membrane of the oocyte & sperm fuse
• this is the official start of fertilization
• after contact the oocyte (previously arrested in metaphase II) completes meiosis II & becomes a mature oocyte

• the start of fertilization (sperm-oocyte membrane fusion) triggers waves of calcium that induce rapid & massive exocytosis of cortical granule contents
• oocyte cortical granule contents modify the zona pellucida through cross-linking & proteolysis (eg. ZP3), making it impenetrable to other sperm
• this is mostly done by lysosomal enzymes from granules
• the cortical reaction produces the block to polyspermy & occurs seconds to minutes after sperm penetration

• oocyte chromosomes decondense & form a pronucleus (+ a 2nd polar body)
• the newly arrived sperm nucleus enlarges & forms the male pronucleus
• pronuclei fuse & all chromosomes start to replicate
• pronuclei membranes break down, chromosomes condense, & line up for the first metaphase
• fertilization is now over - it took about 24 hours
• the zygote is now a unicellular embryo with 46 chromosomes

• the secondary ooctye completes meiosis II
• the normal diploid number of chromosomes is restored!
• determines the sex of the embryo

• when maternal & paternal chromosomes intermingle during metaphase of the FIRST zygotic division
• the pronuclear membranes break down, chromosomes condense, & line up for the first metaphase
• approximately 24 hours after fertilization began

• an egg that has been fertilized by more than one sperm
• several sperm usually begin to penetrate the zona pellucida, but only one enters normally
• although rare, cases of dispermy result in a TRIPLOID zygote
• triploids account for 20% of chromosomally-abnormal spontaneous abortions (SABs)
• only a few complete triploids are born, & survive only a few days