Spermatogenesis. What is it and what does it look like? How do hormones regulate spermatogenesis?

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Clinton Jones
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1 Spermatogenesis What is it and what does it look like? How do hormones regulate spermatogenesis? FSH, androgens, growth factors Animal Physiology (Hill, Wise, Anderson): Ch

2 Spermatogenesis: A bird s eye view How do hormones and growth factors regulate spermatogenesis? proliferation/differentiation restrict apoptosis A cellular development providing highly differentiated cells that transfer a unique, recombined, haploid set of genes to an oocyte 2

3 Mitosis versus Meiosis genetically identical 2. division without DNA replication separation of sister chromatids genetically distinct cross-over separation of homologous chromosomes 3

4 Primordial Germ Cells Primordial germ cell migration Association with Sertoli cell precursors derived from coelomic epithelium on genital ridge; required for germ cell survival in females source of granulosa cells that are also required for germ cell survival 4

Early (Mitotic) Stages of Spermatogenesis: Spermatogonia Stem cell renewal keeps up population of single stem cells undifferentiated spermatogonia cytoplasma bridges; develop in synchrony (germ cell

5 Early (Mitotic) Stages of Spermatogenesis: Spermatogonia Stem cell renewal keeps up population of single stem cells undifferentiated spermatogonia cytoplasma bridges; develop in synchrony (germ cell clones) A paired (2 cells), then A aligned retinoic acid stimulates differentiation of A aligned in spermatogonia A 1 B strictly timed, genetically fixed number of mitotic devisions Number of mitotic cell cycles differs between species RA Final mitosis meiosis 5

division Meiosis-I 24d~28% A(dark) & A(pale): stem cells in primates final S-phase 38d~45% SG

6 Meiosis (human) 1d~1% Meiosis-II Haploid spermatids undergo metamorphosis to spermatozoa human timing 22d~26% spermiogenesis Short-lived spermatocytes II (1d) quickly enter 2nd meiotic division Meiosis-I 24d~28% A(dark) & A(pale): stem cells in primates final S-phase 38d~45% SG prolif. Pachytene -thickness (14d; recombination) Zygotene - bound together Leptotene -slender ribbon 6

bridges serve to share mrnas, using mrna-bps for transport and protection genome blocked BUT many gene products

7 round spermatid Spermiogenesis acrosome most transcription before metaphase II; mrnas protected by proteins not all genes available in all cells midpiece/tail genes on Y-chromosome, absent in half of the cells cytoplasma bridges serve to share mrnas, using mrna-bps for transport and protection genome blocked BUT many gene products needed normal cell self-propelled DNA vector Removal of all superfluous cellular material Maximal compaction of DNA 7

8 Sperm Storage and Capacitation Storage human ca. 2 x 10 8 cells (daily production ~ one ejaculation) nourishment & immobilization Fluid resorption (embryologically derived from mesonephros!) Addition of functionally relevant proteins binding to sperm mobility, egg-tracing & fertilising ability 8

9 Fertilisation in Mammals Chemotactic egg tracing Anchorage on corona radiata granulosa cells; cutting through to zona pellucida Acrosome reaction to digest zona pellucida Entry of male pro-nucleus and extrusion of cortical alveoli 9

10 Spermatogenesis: How Does it Look Like? 10

11 Spermatogenesis: Light Microscopy Characteristic, recurrent associations of developmental steps of germ cells give rise to the stages of the germinal epithelium 11

12 Sertoli cells InTi Testis LM H.s. SeTu Leydig cells SeTu -blood vessels -connective tissue -nerve endings -myoid cells Leydig cells Seminiferous tubules Sertoli cells and germ cells Two or three segments in humans Interstitial tissue different cell types 12

13 Germinal Epithelium (Electron Micros.) Sertoli cells contact germ cells in different stages of development Typical germ cell associations are recurrent in context with strict timing Stages of the epithelium (6 human, rodents) The blood-testis-barrier (Sertoli-Sertoli tightjunctions) segregates meiotic from pre-meiotic cells (spermatogonia) myoid cells and basal lamina contribute to BTB 13

(growth factors) until beginning of puberty, when Differentiation induced by thyroid hormones in conjunction with androgens

14 Sertoli Cells (Mammals and Birds) Germ cells only survive (apoptosis suppressed) when in contact with Sertoli cells Sertoli cell number/proliferation determines spermatogenic capacity FSH stimulates Sertoli cell proliferation via autocrine loops (growth factors) until beginning of puberty, when Differentiation induced by thyroid hormones in conjunction with androgens Differentiated functions support of germ cells during meiosis and spermiogenesis, leading to sperm production and fertility 14

Cystic vs. Non-Cystic Spermatogenesis: Fish & Amphibia vs.

intralobular compartments = cysts A single germ cell

Sertoli Non-Cystic Sertoli cells contact germ cells in

15 Cystic vs. Non-Cystic Spermatogenesis: Fish & Amphibia vs. Birds & Mammals Cystic spermatogenesis Sertoli cells form intralobular compartments = cysts A single germ cell clone develops in synchrony inside a cyst = Leydig = Sertoli Non-Cystic Sertoli cells contact germ cells in different stages of development (i.e. members of different clones). 15

16 Endocrine Regulation of the Sertoli/Germ Cell Unit Stage-wise regulation by hormones? Germ cell genome determines timing No! Hormones allow germ cells, via Sertoli cells, to execute their developmental program LH-R androgen FSH Sertoli (genes?) growth factors Spermatogonia: proliferation, apoptosis Spermiogenesis LH Leydig androgens strictly required, but what for? Disruption of androgen signalling germ cell proliferation, apoptosis AR not in germ but in Sertoli cells (max. VII) AR target genes in Sertoli cells crucial for spermatogenesis not identified yet Estrogens and spermatogenesis ERα in epididymis (fluid resorption) ERβ in germ cells (function?) 16

17 Regulation of Spermatogenesis - Growth Factors # RA -> A pr -> A al -> FSH-stimulated, not FSH-dependent # GDNF stimulated Activin stimulated SCF dependent 17

18 Hormone Receptor Gene Mutants FSH-R/FSHβ Initiation of spermatogenesis retarded; testis smaller; less sperm Sertoli cell number lower, so that reduced growth factor production lower testosterone levels due to reduced paracrine stimulation of Leydig cells Reduced sperm viability and mobility disturbed spermiogenesis misshaped sperm AR Impaired differentiation of Sertoli cells reduced capacity to support germ cells Spermatogenesis interrupted in stage VII of the germinal epithelium development of pachytene spermatocytes spermatid elongation 18

19 Pubertal Activation of the BPG Axis Stimulatory Inhibitory Sex steroid levels low during infancy, yetsufficientto inhibit GnRH secretion GnRH neurons - for reasons yet unknown become more active, despite increasing sex steroid levels (KiSS-1 peptin?) GnRH Gonadotropins allowsincreasedgnrh activity, initially during sleep sex steroids; paracrine factors germ cells 19

To General Embryology Dr: Azza Zaki

To General Embryology Dr: Azza Zaki Introduction To General Embryology The Human Development is a continuous process that begins when an ovum from a female is fertilized by a sperm from a male. Cell division, growth and differentiation transform