Embryologie I OOGENESIS autumn 2024 Oocyte meiosis Zuzana Holubcová Department of Histology and Embryology zholub@med.muni.cz Entry to meiosis MITOTIC-TO-MEIOTIC TRANSITION u Retinole acid (RA) Stra8 meiosin = meiosis initiator oogonium/spermatogonium Mitóza oocyt/spermatocyt Meiotic prophase —^ Ml Mil Pre-leptotene RA BTRA STRA8 I EIOSI differentiation Meiotic initiation Pre-meiotic DNA replication AE formation Meiotic recombination Homolog synapsis Telomere clustering Retinoic acid Meiosis XX - prenatally XY - postnatally Ishiguro et al 2020 Meiosis (1) Premeiotic S phase - DNA replication Meiosis I _ Meiosis II (2) Meiosis I - separation of homologous chromosomes Undifferentiated/stem cell type 9erm cells „prolonged G2 phase" (3) Meiosis II - separation of sister chromatids Meióza Meiosis > Prophase I (1) leptotene Leptonema Sister chromatids^ Sister chromatids -| Nuclear membrane omologous chromosomes Condensation of replicated DNA •7-- >, SYCP3 I MEI4 (2) zygotene Zygonema Synapsis of homologous chromosomes SYCP3|yH2AX . _ f SYCP3 IDMCI or RAD51 (3) pachytene Pachynema (4) diplotene Diplonema S3 Prolonged arrest = dictyatene Recombination of homologous chromosomes (crossing-over) Synapsis disolution -> bivalents with chiasmata d • i \ SYCP3 j MLH1 j SYCP3|vH2AX Meiosis > Homologous chromosomes pairing synapsis = physical association of homologous chromosomes homolous sequence pairing Synaptonemal complex - axial elements - SYCP3+SYCP2 - central element - dimer SYCP1 - lateral elements - cohesins (Rad21, Rec8) gradual formation of SYCP3 a SYCP2 foci axial element built by coalescence of SCP3 and SCP2 foci with cohesin complex proteins axial element stabilized by cross-linking with SYCP1 dimer, which forms central element Synapsed Unsynapsed Sycpl Sycp3 Sycp2 Harmadl •iinniiüiiuL«™^--. • •••••• V/' " Preleptotene Sister Chromatids Homologous Chromosomes 9 Axial/Lateral Element associated proteins / Central Element associated proteins Leptotene Zygotene Pachytene Diplotene Central Element Isynaptonemal ^Jchiasma -[JComplex from Moms and Purlman 1988 Meiosis > Homologous chromosomes pairing - pairing of distant homologous chromosomes accomplished by congregation of telomeres attached to nuclear membrane -> tzv. „telomere bouqouet" C h ro mosom e movem en t Bouquet Bouquetexit Ishiguro 2018 Telomere bouquet Axial elements Berrios et a 12013 1 i □ b Non-specific telomere associations Stable pairing near chromosome ends Stable pairing extends Synapsis initiates and extends Leptotene-zygotene Zygotene bouquet Zhou et al 2012 Elkouby and Mullins 2017 Meiosis > Homologous recombination 8 2 Q. 4> C c c 4> 2 a c s 1 c V mciotic axis formation DSB Ibnnation i 5' end resection ..........•••••»••«••»•••«••••••••••(I presynaptic : alignment ............. V ■•■••■••••••••••••^ single strand invasion : VllllfltfltfKtllMllfllMMIItll synapsis initation DNA synthesis .A................. second end capture full synapsis l : - ^'-"double Holliday j junction formation i X class I crossover Meiosis > Homologous recombination - DNA double strand breaks (DSB) precede synapsis formation Meiosis > Homologous recombination PRDM9 - histon metyltransferase - recognition and epigenetic modification of specific DNA sequences (recombination hotspots) prdm9 Spoil ^ | - DNAendonuclease I.........../A^WLrn - its dimer forms DSB sp011 - each monomer then binds 5' end of ssDNA - Spoll+oligonucleotide cleaved away by exonuclase -> free 3'end prdm9 111111111 II I <------i ? 9 I I I I I n I I I I I I I I I I I I z. MRX complex MRX complex 3' ssDNA overhangs ~'~ 35 nrrp-3' ?_Inn I mouse Spoil-/- males sterile spoi 1 oiigo Spoil polymorfism in male infertility release 1 oligo Iff" Meiosis > Homologous recombination PRDM9 RPA (replication protein A) - binds free 3'end - recruits DMC1 and Rad51 - during invasion binds DNA template strand and stabilizes D-loop Spoil DMC1 + Rad51 - meiotic recombinases - bind and navigate free 3'end of ssDNA to invade dsDNA of homologous chromosome Broken chromosome Spoil RPA DMC1 RAD51 RPA D-loop RPA binds template in D-loop DMC1 performs strand exchange RPA binds broken chromosome DMC1 binds near, RAD51 away from break D-loop localisation resembles crossover gene-conversions Yeast RecA homologue Hinch et al 2020 Meiosis > Homologous recombination - DNA syntesis of DNA 3'end using ■ non-sister chromatid as a template + strand ligation ■ DSB 3' 5' 5'end resection Synthesis dependent strand annealing (SDSA) Single end invasion (SEI) Double strand break repair (DSBR) Meiosis > Homologous recombination ■ Holliday junction (HJ) - named after Robin Holliday, who proposed its existence in 1964 - DNA duplex - physical linkage of two DNA doublehelixes intermediate of homologous recombination and DSB repair mechanism - visible in electron microscope - HJ can move, double HJ can be resolved Robin Holliday HJ .....mm;........................... lllltlllllllt llllllllllllllltllllllltllllllli llllllllllllir l!l!l!!!l!(!l!l!l!i!!!l!l!i!l!l Branch migration JHIIHIIUIIIIHIIHIIIIHUHIII Meiosis > Homologous recombination (a) DSB m non-crossover ~ 90 - no gene conversion (c) (a) D-loop resolution -> DNA synthesis according to complementary strand (b) convergent branch migration resulting in resolution of HJs (c) strand exchange and HJ resolution without gene conversion D' ď X T Hollidayjunction enzyme resolvase Vertical cut (along line V) and rese crossover ~10% - gene conversion occurs at both chromatids - HJ resultion produces new combination of genes https://www.youtube.com/watch?v=3qgBKrAZCLg if) 5' 3' 3' 5' D' ď e' E' e F Heteroduplexes and recombinants (b) ........ e1 X e Horizontal cut (along line H) and reseal f1 d e f Heteroduplexes; No recombinants Meiosis > Homologous recombination ■ Chiasmata (chi-structure) - physical contact sites of homologous chromosomes marking crossing-over regions - visible after synaptonemal complex disolution during diplotene links homologous chromosomes together in the form of bivalents (tetrades) - disapprear as homologous chromosomes separate during anaphase I - sex differences in location and number of chiasmata (more distal in males) - altered number of chiasmata and location of chiasmata associated with aneuploidy Centromere Prometaphase 1 Homologous pairs of chromosomes L are held together at the chiasmata. Anaphase I Homologous pairs of chromosomes are pulled apart by * A £, A microtubules %\ Ml mk mt attached to the W Mj ■ kinetochore. | y / ^^^^L Microtubules attach to the fused kinetochores of the sister chromatids Sister chromatids remain attached at the centromere. Regulation of meiotic prophase overview 5islcr Chromjuds Centromere Leptonema Homolog pairing DSB formation UncMa SpoH SycplSycp3 Mrell RadSO-Nsb I RřCÍ Mti! Smclfi Synapsis Syttl.2 Sycpl Ttxl2 Hoimadl, 2 Zygonema DSB processing Dmcl Radii yH2AX Pachynema Recombination Monitoring Mihl, Mlh} Atn\Atr MsM.MihS Tnpll Mvit 1. £me 1 free I Blm,ftnt212 bicA Diplonema Desyrapsis and entry into dictyate arrest (Vřítí Ubb Meiotic arrest. Follicle formation Defective crossing over devoid of primordial follicles infertile Chromatin configuration during diplotene arrest dictyate stage = prolonged diplotene arrest chromosomes become dispersed, less distinct and form faint network germinal vesicle (GV) = prophase nucleus - ~30-40 |im nucleoli* = „nucleolar-like body (NLB)" „nuclear remnant" - structure containing electron dense fibrilar/granular material during oocyte growth phase, chromosomes decondense and chromatin becomes transcriptionally active allowing for accumulation of cellular mass GV NGO Qian and Guo 2022 Large scale chromatin remodelling Nonsurrounded nucleolus (NSN) Chromatin Hoechst 33342 Transcription BrUTP Partily-surrounded nucleolus (partly-NSN) intermediate Surrounded nucleolus (SN) nnuclear rim of heterochromatin = karyoplast folicules preantral/antral antral antral Pesty et al 2007 Large scale chromatin remodelling - bidirectional GCs-oocyte comunication is necessary for timely coordination of chromatin decondensation and onset of transcriptional silencing Resumption of meiosis LH Surge {+ Feedback) (mU'ml] Eh 300- 0. 4 Follicle £o Diameter ^ (mm) f £H ^^LH,^ ^Ovulation (Day 13-14) r 0 2 4 6 8 10 12 144 16 18*20 + 22 24 26 28 ovarian follicle 1^ estrogen the gene Gja4 which encodes for Cx37 is upregulated in the oocyte, and Gja1 is upregulated in the cumulus cells upon fsh. Cx37 connects the oocyte with the projections of the cumulus cell which go through the zona pellucida \7 LH surge \7 oocyte-cGCs uncoupling \7 release from GV arrest FSH stimmulation LH immediate response LH late response granulosa cells with increasing riumberofgap-junctions formed by Cx43 granulosa cells show high numberof gap-junctions prior to LH surge disruption and loss of gap-junctions upon the phosphorylation ofCx43 inhibition ofCx43 translation and seperation of granulosa cells Kordowitzki et ol 2021 Control of prophase arrest = NPPC - C-type natriuretic peptide CNP NPR2 Autonomous cAMP production GPR3 AC III Supplementation of cGMP by cGCs balances cAMP degradation by PDE Prophase arrest is dependent on high levels of cAMP in ooplasm * Oocyte incubation in cAMP analogs or PDE inhibitors prevents spontaneus maturation in vitro Resumption of meiosis A Before Luteinizing Hormone Expression BMP15 and GDF9 dependent gap junction plaques zona pellucida After Luteinizing Hormone cGMP decreases Resumption of meiosis Decrease of NPPC production (l) Gap junction closure (2) AN -/•A Nuclear maturation chromosomal segregation polar body (PB) extrusion MM arrest 2n 4C oocyte -> In 2C egg > Cytoplasmic maturation structural and functional modification of organelles global changes in organelle arrangement mRNA translation and posttranslational modifications synthesis/degradation of maternal factors Acquisition of fertilization and developmental competence Nuclear maturation in mammalian oocytes (1) Nuclear envelope break-down (2) Chromatin condensation and chromosome individualisation (3) Chromosome alignment at spindle (4) Homologous chromosome segregation (asymmetic cytokinesis) (5) MM spindle formation - MM arrest MAP4 - microtubules H2B- DNA J4.V/--v-^'• 0.00 h 10 urn Schuh and Ellen berg, Cell 2007 12 hours 0.00 h_ ~ 24 hours Nuclear maturation in human oocyte Nuclear envelope breakdown Onset of microtubule nucleation Growing microtubule aster Early bipolar spindle Initial chromosome congression Stable chromosome alignment Anaphase Polar body abscission Bipolar Mil spindle ✓" * *■ i' ! W * % • 0 w ě r * '».V. H J* < • r — i 1 1 1 - ' _0 h:0 min ■ aii »-' 15:20 .v. L _ J 17:50 18:30 1 • 1* L mm mt 24:50 ■ Chromosomes 1 □ Microtubules B i i i i i i i i IR Time after nuclear envelope breakdown (h) 3 on o cn o cn o c 38 38 38 35 17 38 38 34 h * * * ^ ^ ^ 4.7 ±1.4 5.4 ±1.4 6.8 ±1.6 13.5 ±3.0 16.3 ±2.3 17.5 ±2.3 20.2 ± 2.6 23.0 ± 3.2 Holubcová et al Science 2015 Nuclear maturation in human oocyte ♦> Chromosome clustering - transient stage of chromatin aggregation - after NEBD and before onset of spindle assembly Nuclear envelope Chromosome Chromosome breakdown compaction cluster o s> c GO ft _ 0 min 10 # 20 i Chromosomes Onset of Chromosome NEBD chromosome migration cluster Mehna Schuh Chromosome Onset of Growing GV cluster spindle assembly microtubule aster Bipolar spindle #H 11 % n h nn min 0:30 1:00 1:30 3:00 ■ Chromosomes ■ Microtubules ^6 in * J i" " i f*- * * - - - -yf 0 mm 5 10 20\ ■ Chromosomes □ F-actin (EGFP-UtrCH) actin cables invade disassembling nucleus and drive chromosome coalescence Harasimov et al, Nature Cell Biology 2023 Nuclear maturation in human oocyte ♦> Chromosome clustering - promotes rapid capture of chromosomes by acentrosomal spindle and prevents chromosome losses in the long gap phase between nuclear envelope breakdown and the onset of spindle assembly Spindle assembly in mammalian oocytes NEBD Chromosome clustering Chromosome cluster Onset of spindle formation Early bipolar Ml spindle P^rc^^^o^y^Í^^^^^rn^ Human oocytes: 0 min 5 min 30 min 30 min Lamina remnants persist around the chromosomes until aster formation. _1 40 min 5 h 24 min 4 h 50 min 6 h 48 min Chromosome clustering ensures rapid and complete chromosome capture by the newly assembling spindle Actin cables form in the former nuclear region Actin cables move the chromosomes as they migrate centripetally Actin cables form and Microtubules move migrate centripetally until the chromosomes that were not cluster has formed clustered by actin cables 1. Actin cables interact with First microtubules appear chromosome surface 5 min 6 min 2. Actin cables interact with kinetochores 15 min 30 min Legend Nuclear pore complex Nuclear lamina Chromatin Nucleolus Kinetochore Bivalent kinetochore Actin filaments assembled by Formin-2/Spire Microtubules CD ■ < c in c E 0 co 1

haploid egg (MM oocyte) > Meiosis I Metaphase II ii II Biorentation of sister centromeres 1st Polar body WS Reductional segregation Anaphase II Centromeric cohesin cleaved > Meiosis II single chromatid 2nd Polar body Pronuclei Fertilized zygote separation of homologous chromosomes haploid set of chromosomes eliminates to 1st PB 2n 4C In 2C separation of sister chromatids one set of chromatids eliminated to 2nd PB In 2C -> In 1C (+ In 1C from sperm) Kinetochore-microtubule attachment > MITOSIS/ MEIOSIS II back-to-back arrangement of sister kinetochores attachment: kinetochores in relation to spindle poles orientation: chromosome in relation to spindle poles > MEIOSIS I side-by-side arrangement of sister kinetochores sister kinetochores attached to opposite poles amphitelic bi-orientation only one of the sister kinetochores attached to one pole both sister kinetochores attached to the same pole one of the sister kinetochores attached to both poles monotelic (monotelic) mono-orientation syntelic (syntelic) mono-orientation merotelic (merotelic) bi-orientation amphitelic attachment (biorientation) during Mitosis & Meiosis II H 4 mono-orientation of sister kinetochores bi-orientation of sister kinetochores (side-by-side arrangement can be preserved or not) bi-orientation of bivalent mono-orientation of bivalent amphitelic attachment (biorientation) during Meiosis I - sister chromatid monoorientation (behave like functional unit!) Anaphase entry Dephosphorylated Thr-14 and Tyr-15 Phosphorylated Thr-14 and Tyr-15 Separase-mediated cleavage of cohesins B. MEIOSIS Cohesin Pericentromere Kinetochore Centromere Chiasma Separase (Esp1 Securin (Pdsl) 4/ CDKl activity Anaphase Promoting Complex (APC) Metaphase I Metaphase II Anaphase II -v- Meiosis I -y- Meiosis II Anaphase entry > MITOSIS - Mitotic Checkpoint Complex (MCC) on unattached kinetochores prevent Anaphase Promoting Complex (APC) from cyclin B and securin destruction Prometaphase 8 Unattached kinetochores catalyse MCC formation MQ Mitotic Checkpoint Complex ♦>Spindle assembly checkpoint (SAC) - the pathway that delays mitosis until kinetochores are attached to microtubules all kinetochores must be occupied APC/C activation in minutes low aneuploidy rate role of interkinetochore tension Chromosome Spindle Kinetochore Metaphase Anaphase MCC blocks APC/C activation Mitotic exit Degradation of Cyclin B1 Mono-orientation Syntelic attachment No tension ■ Bi-orientation Amphitelic attachment Tension + Misaligned Chromosomes Chromosome bi-oriGntation Chromosome Segregation KT-MT attachment J stable Turnover of KT-MT I attachment stops Aurora B kinase i Spindle pole & microtubule (MT) Q Cohesin Kinetochore (KT) Q Aurora B targets phosphorylated Aurora B targets dephosphorylated Anaphase entry Cohesin > MEIOSIS I Prophase I Recombined Homologous (Maternal and Paternal) Chromosomes r? APC I < securin Separase inactive separase cleaves Rec8 cohesion ring opened Anaphase I Chiasma Homologous Kinetochore Co-orientation Shugoshin (Sgo) - Japanese „guardian spirit" Loss of cohesion in anaphase I > MEIOSIS I Metaphase I (D) Cohesin Sister centromeres Sister kinetochores Anaphase I Meiosis II Meiotic Exit Stabilizes location of Sgo Ensures chromosome alignment in MM Kim etal 2015. Maier et o\, 2021 Shugoshin (Sgo2) recruits PP2A, which removes Rec8 phosphorylation, making it a poor substrate for separase-dependent cleavage. Metaphase 1 Anaphase I onset Late Anaphase 1 / Telophase 1 SUM02/3 Sgo2 Separase Remover (unknown) ^Y"" />? \ «■Uli Shugoshin Sgo2 Stabilizes Sgo2 Dingetal, 2018 Anaphase entry > MEIOSIS I tcinetochofe cenlromete prophase SAC? S 2 a-1 1-II metaphase I SISTER KINETOCHORE COORIENTATION HOMOLOG BIORIENTATION (CHIASMA-DEPENDENT) metaphase I SISTER KINETOCHORE BIORIENTATION I n o anaphase II Marson and Wassmann 2017 Weakened SAC ?? 00:00 hrs Chromosomes (H2B-mRFP) Microtubules MAP4-EGFP) Zielinska et al. eLife 2015. SAC in human oocytes is permissive Bi-directional, no lagging Bi-directional, with lagging D * Tri-directional anaphases as a novel chromosome segregation defect in human oocytes Jenna Haverfield11, Nicola L. Dean1,1, Diana Noel1, Gaudeline Remillard-Labrosse1, Veronique Paradis3, Isaac-Jacques Kadoch2,1, and Greg FitzHarris1,2'* ...... .-------------- 1. ...... . j, ..i , , M (CM] du CHJM. HgcU. QuMm . CmU WJ1 «1 Bi-directional, with chromatin mass separation Tri-directional, with or without lagging - misaligned chromosomes do not block anaphase I onset Tripolar anaphase may result in (1) reunion of 2 chromosomas masses in the aneuploid oocyte, 3rd mass extruded to the PB (1) re-joining of chromatin and cytokinesis failure (seemingly non-maturing Ml !) Havrfield et al. 2017. Bi-directional, no lagging Bi-directional, with lagging Bi-directional, with chromatin separation Tri-directional Chromosomes re-joining after cytokinesis Pbi yte 1 1 Greg FitzHarris Oocyte Chromosomes re-joining in the absence of cytokinesis SAC in human oocytes is permissive Control Etoposide [100 Mg/ml] 100 — 80 60 B 40 O 20 12 3 4 Time post release (h) 0 100 Etoposide [ug/ml] 24 Exposure (h) 24 Exposure (h) Induced DNA damage does not prevent anaphase entry in human oocytes - Human oocyte with DNA damage harbour abnormal spindles but exhibit apparently normal morphology! Remillard-Labrosse et al. 2019. 0) 3 0) £ CO O Co x w CU > 3 CD 2 I I o o ^ >^^ . ^^^^^ 9 / \ I V f If •* •* Modes of SAC functionality - in somatic cells, one unattached kinetochore capble to activate SAC1 - DNA damage prevents entry to mitosis but not anaphase - mouse oocytes with DNA damage undergo GVBD but arest in Ml and fail to extrude PB2 - lack of response to unaligned chromosomes and lack of tension3 in human oocytes, neither misaligned chromosomes nor DNA damage activate robust SAC response42 only severe spindle disruption can prevent PB SAC signalling machinery is present5 BUT inefficient to prevent anaphase onset when one or a few chromosomes are not congressed and attached to kinetochores 1 Kuhn & Dumont, 2019; Rieder et a I.,1994 2 Remillard-Labrosse et al. 2019 3 Gui & Homer, 2012; Kolano et al., 2012; Lane et al., 2012; Nagaoka et al., 2011; Šebestová et al., 2012 4Zielinska et al 2015, Havrfield et al. 2017 5 Lagirand-Cantaloube et al, 2017 Cytoplasmic volume affects SAC stringency cytoplasm scales the spindle and affects the timing of anaphase onset and efficiency of chromosome alignment oocytes with decreased cytoplasmic size have spindles with better-focused poles and higher SAC stringency large cytoplasmic volume dilutes the nuclear factors, including anaphase inhibitors, thus resulting in the failure of the spindle to induce a checkpoint arrest in response to a small number of misaligned chromosomes Developmental Cell Article Large Cytoplasm Is Linked to the Error-Prone Nature of Oocytes Tomoya Kitajima Hirohisa Kyogoku1 and Tomoya S. Kitajima1'2'* 'Laboratory for Chromosome Segregation, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan 2Lead Contact 'Correspondence: tkitajima@cdb.riken.jp http://dx.doi.Org/10.1016/j.devcel.2017.04.009 Halved GV oocyte (Prophase I] Meiotic resumption 0. Control Doubled \___/ CytoplasmicV J Fusion with removal \____' enucleated removal — oocyte 4^ c Monitor meiosis I Oocyte cytoplasmic size Halved Control Doubled Pole integrity 1 ■----- + (Spindle checkpoint = Chromosom« segregation error | Kyogaku and Kitajima, Developmental Cell, 2017. Chromosome segregation errors Oocyte aneuploidy Diakinesis Anaphase I Normal meiosis Whole chromosome nondisjunction Metaphase II Predivision Balanced chromatid separation Predivision Oocyte I Polar body Extra chromosome Chromosome nondisjunction (NDJ) Extra chromatid Separated chromatids Separated chromatids Precocious separation of sister chromatids (PSSC) Chromosome lagging delayed chromosome/chromatid movement during anaphase risk of inaccurate segregation, chromosome loss/gain and aneuploidy Metaphase Sister chromatids Anaphase Chromatin .5 Kinetochore/V Ubt* — | Lagging CtMMMMNM Normal anaphase Lagging chromosomes losomes Chromatin bridge iIm* "I .r No lagging Class I laggards Class II laggards Mihajlovic et al 2021 Transition from meosis I to meiosis II GV arrest Oocyte maturation Metll arrest CDK1 activity Follicle growth External /internal trigger eiosis Meiosis ii CDK1 cycB CDKl CDKl cycB í t i LH or denudation SAC satisfaction Cytostatic factor - CSF T sperm Metaphase II arrest ^ Emi2 (Early Mitotic Inhibitor) - meiosis specific inhibitor of APC (^cytostatic factor" - CSF) - required for establishment and maintanance of MM arrest in mammalian oocytes - phosphorylation needed to keep Emi2 stable Magwick et al 2006 > Btg4 contributes to APC/C inhibition by controling protein expression during MM arrest expression of Emi2 is perturbed when BTG is absent (RNAi - depletion) Pasternak et a 12016 714 Cdc25 i^jpCyc CAK B 0 B Cdc2 Wee1 Cdc2 >1R1 Myt1 T161 Oocyte Maturation Egg Fertilization Embryo - Mil arrest reached hours before ovulation and maitained for ~ 24 hours Mil arrest release > Calmodulin dependent protein kinase II (CAMKM) - activated by Ca2+ signal at fertilization - phosphorylates Emi2 causing its degradation - activates WeeklB kinase that phosphorylates CDK1 contributing to its inactivation 2" > CaM Emi2 I Emi2 - WeelB CDKl Inactive Active cycB Fertilization stage in different species Primary diploid oocyte 2n 4C Flatworms Roundworms First metaphase 2n 4C Molluscs Insects Second metaphase First meiotic division In 2C Amphibians Mammals Second meiotic division Haploid egg In 1C Coelenterates Echinoderms Examples of organisms that are fertilized at the stage of meiosis indicated U IM I ED https://is.muni.cz/do/med/el/ake/index.htm e-Atlas klinické embryológie - CZE/ENG e-learningová pomůcka - veřejně dostupné po zadání hesla M U N I e-Atlas klinické embryológie PharmDr. Zuzana Holubcová, Ph.D. Ústav histologie a embryológie. Lékařská fakulta MU Uvod Tento atlas je e-learningovým materiálem primárně určený studentům výukového programu Embryológ ve zdravotnictví. Lékařské fakulty, Masarykovy univerzity. Představuje kolekci dříve nepublikovaných fotografií a videi lidských oocytů a ranných embryí vzniklých v rámci procesu umělého oplozeni. [25071978 ft = datum narození Luise Brown (DDMMYYYY) Cílem této práce je seznámení s morfologickou variabilitou ženských pohlavních buněk a embryí a zachycení dynamiky preimplantačního vývoje. Poděkování patří klinikám Reprofit International (Brno) a IVF clinic (Olomouc) za poskytnutí použitého obrazového materiálu. flED.MUIIl.cz