Royal Hospital for Women - Reproductive Medicine Seminar 2018

Embryology - 3 Jun 2024        Expand to Translate
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Adult endocrine organs

Introduction

This is the partial online draft version of my presentation, as there was no internet I switched to powerpoint fversion or the final presentation. I will though update this online version as it will include full access to molecular data and all animations presented in my talk.

Powerpoint Slides: 1 slide/page PDF | 4 slides/page PDF

Requested Lecture Content
Dr Rachael Rodgers - "Male and female reproductive/urogenital systems, breast, thyroid, adrenals, kidneys, hypothalamus and pituitary, it would be perfect."

Background

• Uterine Tube Biobank (Prof Ledger)
  • Molecular aspects of ectopic implantation
• Trophoblast differentiation
  • Control of implantation and early placentation
• Digital Embryology Consortium
  • The objective of this international partnership is to digitise, preserve, and make available for researchers the major embryology histological collections.
• Kyoto Collection(eBook)
  • with Shiota, Yamada and Ho.
• Human SEM (eBook)
  • in preparation with Sulik, Vekemans and Attié-Bitach.
• UNSW Embryology

Reproductive

Timeline

Gestational Age GA Week	Event	Fertilization Age Week
5-6	primordial germ cells migrate during gastrulation	3-4
6	intermediate mesoderm, pronephros primordium	4
7	mesonephros and mesonephric duct (Wolffian duct)	5
8	ureteric bud, metanephros, genital ridge	6 (35 days)
9	cloacal divison, gonadal primordium - indifferent to first appearance of testis cords	7 (42 days)
10	paramesonephric duct (Mullerian duct), clear gonadal differentiation	8 (49 days)
11	paramesonephric duct fusion (female)	9 (56 days)
17	primary follicles (ovary)	15 (100 days)

Primordial Germ Cells

Primoridal Germ Cell Migration

Primordial Germ Cells (PGCs) are thought to be the first population of cells to migrate through the primitive streak in early gastrulation.

Human Embryonic Disc (Stage 7 GA week 5)

GA Week 5

• Human embryonic disc showing the primitive streak region where gastrulation occurs, generation the trilaminar embryo.
• Arrows indicate direction of cell migration through the streak.

This population of cells then lie at the hindgut and yolk sac junctional region and later migrate into the germinal ridge in early embryonic development.

Human Embryo (Stage 9 GA week 5) primordial germ cell region (green)

• Sacrococcygeal teratomas - Remnant primitive streak cells (most common solid tumor in newborn infants)
• Germline teratoma - (Germinoma) abnormally differentiated/located PGCs fail to die.

Mouse PGC Migration

E9.5	E10.5
<html5media height="400" width="400">File:Primordial_germ_cell_002.mp4</html5media>	<html5media height="400" width="400">File:Primordial_germ_cell_003.mp4</html5media>

PGC motility 3 phases - initiation, migration and stopping

• based upon normal actin cell motility.
• no sex-specific differences

PGC Chemoattraction

Chemoattraction Ligand SDF-1 (Stromal cell-derived factors 1, now CXCL12, C-X-C motif chemokine ligand 12) expressed in the genital ridges and surrounding mesenchyme. Receptor CXCR4 (C-X-C motif chemokine receptor 4) expressed by PGCs. See also reviews of PGC migration

Stromal Derived Factor 1 (SDF-1, CXCL12) chemotaxis <html5media width="400" height="300">https://www.youtube.com/embed/tqlc_YAtWRE</html5media>

Intermediate Mesoderm

Mesoderm Generation (chicken) <html5media height="700" width="300">File:Chicken presomitic mesoderm 03.mp4</html5media>	Human trilaminar embryo {"Germ layers") Intermediate mesoderm derives genital and renal systems.
	<html5media height="520" width="360">File:Urogenital_sinus_001.mp4</html5media> GA week 6-7 Urogenital Sinus Movie

It is not the primordial germ cells which respond to SRY presence or absence, but the supporting cells within the developing gonad.

Urogenital Septum

<html5media height="440" width="420">File:Urogenital_septum_001.mp4</html5media> Click Here to play on mobile device

GA Week 8 Initially the cloaca forms a common urinary, genital, GIT space This is divided by formation of a septum into anterior urinary and dorsal rectal superior - Tourneux fold lateral - Rathke folds septum fuses with cloacal membrane before it commences to degenerate. hindgut - distal third transverse colon, descending and sigmoid colon, rectum. anal pit - distal third of anorectal canal (ectodermal)

Mouse Gonad

Sertoli and Germ Cells

Sry Signaling

• red - Sertoli cells, showing Fgf9 expression (following Sry expression FGF9 is a downstream signaling molecule).
• green - Germ cells and endothelial cells, showing PECAM expression.

Genital Ridge (early embryo)

• green - gonadal supporting cells
• blue - Sertoli cells (male)
• pink - pre-granulosa cells (female)

RSPO1 R-Spondin Family, Member 1

Sex Development Genes

Mammalian Sexual Development Genes
Gene (OMIM)	Protein Function	Gonad Phenotype of Null Mice	Human Syndrome
Bipotential gonad
Wt1	Transcription factor	Blockage in genital ridge development	Denys-Drash, WAGR, Frasier syndrome
Sf1	Nuclear receptor	Blockage in genital ridge development	Embryonic testicular regression syndrome
Lhx9	Transcription factor	Blockage in genital ridge development	a
Emx2	Transcription factor	Blockage in genital ridge development	a
M33	Transcription factor	Gonadal dysgenesis	a
Testis-determining pathway
Gata4/Fog2	Transcription/cofactor	Reduced Sry levels, XY sex reversal	a
Sry	Transcription factor	XY sex reversal	XY sex reversal (LOF); XX sex reversal (GOF)
Sox9	Transcription factor	XY sex reversal	Campomelic dysplasia, XX sex reversal (GOF)
Sox8	Transcription factor	XY sex reversal in combination with partial loss of Sox9 function	a
Fgf9	Signaling molecule	XY sex reversal	a
Dax1	Nuclear receptor	Impaired testis cord formation and spermatogenesis	Hypogonadism
Pod1	Transcription factor	XY sex reversal	a
Dhh	Signaling molecule	Impaired differentiation of Leydig and PM cells	XY gonadal dysgenesis
Pgdra	Receptor	Reduction in mesonephric cell migration	a
Pgds	Enzyme	No phenotype	a
Arx	Transcription factor	Abnormal testicular differentiation	X-linked lissencephaly with abnormal genitalia
Atrx	Helicase	ND	ATRX syndrome
Insl3	Signaling factor	Blockage of testicular descent	Cryptorchidism
Lgr8	Receptor	Blockage of testicular descent	Cryptorchidism
Hoxa10	Transcription factor	Blockage of testicular descent	Cryptorchidism
Hoxa11	Transcription factor	Blockage of testicular descent	Cryptorchidism
Amh	Hormone	No Müllerian duct degeneration	Persistent Müllerian duct syndrome
Misrl1	Receptor	No Müllerian duct degeneration	Persistent Müllerian duct syndrome
Pax2	Transcription factor	Dysgenesis of mesonephric tubules	a
Lim1	Transcription factor	Agenesis of Wolffian and Müllerian ducts	a
Dmrt1	Transcription factor	Loss of Sertoli and germ cells	XY femaleb
Ovary-determining pathway
Wnt4	Signaling molecule	Müllerian duct agenesis, testosterone synthesis, and coelomic vessel formation	XY female (GOF)
FoxL2	Transcription factor	Premature ovarian failure	BPES
Dax1	Nuclear receptor	XY sex reversal (GOF)	XY sex reversal (GOF)
RSPO1	Signaling molecule	XX sex reversal (LOF)	XX sex reversal (LOF)
Table Legend
	BPES - blepharophimosis-ptosis-epicanthus inversus syndrome GOF - gain-of-function mutation LOF - loss-of-function mutation ND - not determined WAGR - Wilms' tumor-aniridia-genitourinary malformations-mental retardation		a No mutations in human sexual disorders identified to date. b Candidate gene for 9p deletion, XY sex reversal.
Table data modified

Note new HUGO Gene Nomenclature Committee (HGNC)

• Male sex - SF-1 (NR5A1) Nuclear Receptor Subfamily 5, Group A, Member 1
• Female sex - DAX-1 (NR0B1) Nuclear Receptor Subfamily 0, Group B, Member 1

Stages

1. Development of the indifferent gonad - (genital ridge) early embryo
2. Differentiation of gonad - (testis or ovary) late embryo, defining event in sexual differentiation
3. Differentiation of internal genital organs and ducts - late embryo to fetal
4. Differentiation of external genitalia - fetal
5. Development of secondary sexual characteristics - puberty

Male – Sertoli Cells

• Human SRY activation not known
• Mouse SRY activation - Wilms tumor 1 (Wt1), GATA binding protein 4 (Gata4), zinc fnger protein, fog family member 2 (Zfpm2), chromobox homolog 2 (Cbx2), mitogen-activated protein kinase 4 (Map3k4), insulin receptors.
• SRY activates key transcription factor SOX9 in Sertoli cells
  • Sertoli also express SOX9, FGF9, and PTGDS (lipocalin-type prostaglandin D2 synthase, catalyzes conversion of prostaglandin H2 to prostaglandin D2)
• SOX9 requires positive regulatory loop
• Sox9 and FGF9 feed-forward loop upregulates Fgf9 expression
• repression of a WNT4
• Retinoic acid (RA) - required later for Sertoli to germ cells essential for adult mammalian spermatogenesis.

Human SOX Family

Table - Human Sox Family Approved Symbol Approved Name Previous Symbols Synonyms Chromosome SOX1 SRY-box 1 13q34 SOX2 SRY-box 2 3q26.33 SOX3 SRY-box 3 PHP Xq27.1 SOX4 SRY-box 4 6p22.3 SOX5 SRY-box 5 "L-SOX5, MGC35153" 12p12.1 SOX6 SRY-box 6 11p15.3 SOX7 SRY-box 7 8p23.1 SOX8 SRY-box 8 16p13.3 SOX9 SRY-box 9 "CMD1, CMPD1" SRA1 17q24.3 SOX10 SRY-box 10 "DOM, WS4, WS2E" 22q13.1 SOX11 SRY-box 11 2p25.2 SOX12 SRY-box 12 SOX22 20p13 SOX13 SRY-box 13 "Sox-13, ICA12, MGC117216" 1q32.1 SOX14 SRY-box 14 SOX28 3q22.3 SOX15 SRY-box 15 SOX20 "SOX27, SOX26" 17p13.1 SOX17 SRY-box 17 8q11.23 SOX18 SRY-box 18 20q13.33 SOX21 SRY-box 21 SOX25 13q32.1 SOX30 SRY-box 30 5q33.3 SRY sex determining region Y TDF Yp11.2     Links: Developmental Signals - Sox | OMIM | HGNC | Tbx Family | Bmp Family | Fgf Family | Pax Family | R-spondin Family | Sox Family | Tbx Family

Female - Granulosa Cells

Female

• Wnt4 (1p36.12) secreted protein, inhibit testis-specific processes
  • mesonephros migration of endothelial cells
  • repress steroidogenesis by Sf1 or blocking recruitment of steroidogenic cell precursors
• RSPO1 (1p34.3) secreted protein
  • agonist WNT4 signalling
• FOXL2 (3q22.3) transcription factor
  • repress Sox9 by synergistic interaction with estrogen receptors α and -β (ER-α-β)
  • postnatal follicle development and female fertility maintenance

Human WNT Family

Table - Human Wnt Family Approved Symbol Approved Name Previous Symbols Synonyms Chromosome WNT1 Wnt family member 1 INT1 12q13.12 WNT2 Wnt family member 2 INT1L1 IRP 7q31.2 WNT2B Wnt family member 2B WNT13 XWNT2 1p13.2 WNT3 Wnt family member 3 INT4 "MGC131950, MGC138321, MGC138323" 17q21.31-q21.32 WNT3A Wnt family member 3A 1q42.13 WNT4 Wnt family member 4 WNT-4 1p36.12 WNT5A Wnt family member 5A hWNT5A 3p14.3 WNT5B Wnt family member 5B 12p13.33 WNT6 Wnt family member 6 2q35 WNT7A Wnt family member 7A 3p25.1 WNT7B Wnt family member 7B 22q13.31 WNT8A Wnt family member 8A WNT8D 5q31.2 WNT8B Wnt family member 8B 10q24.31 WNT9A Wnt family member 9A WNT14 1q42.13 WNT9B Wnt family member 9B WNT15 WNT14B 17q21.32 WNT10A Wnt family member 10A 2q35 WNT10B Wnt family member 10B "WNT-12, SHFM6" 12q13.12 WNT11 Wnt family member 11 11q13.5 WNT16 Wnt family member 16 7q31.31     Links: Developmental Signals - Wnt | OMIM Wnt1 | HGNC | Bmp Family | Fgf Family | Pax Family | R-spondin Family | Sox Family | Tbx Family | Wnt Family Human Chromosomes: 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | X | Y

Adrenals

• Week 6 - fetal cortex, from mesothelium adjacent to dorsal mesentery; Medulla, neural crest cells from adjacent sympathetic ganglia
• Fetal Adrenals - fetal cortex later replaced by adult cortex
• Adult cortex - mesothelium mesenchyme encloses fetal cortex

Adrenal Cortex

• Late Fetal Period - differentiates to form cortical zones
• Birth - zona glomerulosa, zona fasiculata present
• Year 3 - zona reticularis present

Adrenal Medulla neural crest origin, migrate adjacent to coelomic cavity, initially uncapsulated and not surrounded by fetal cortex, cells have neuron-like morphology 2 cell types - secrete epinepherine (adrenaline) 80%; secrete norepinephrine (noradrenaline) 20%

‎‎Adrenal Medulla Page | Play

Links: Endocrine - Adrenal Development | Endocrinology - Adrenal Cortex Development | Endocrinology

Hypothalamus

Hypothalamus is a neuroendocrine organ linking the brain to the endocrine system. There are also hypothalamic cells that hormone-responsive during development and in the adult. Recently there has been shift in describing neurological development from the traditional morphological model of “primary and secondary vesicles” with developmental origin and gene expression model “prosomeric development”

• Neuroectoderm - prosenecephalon then diencephalon after induction by the underlying prechordal plate.
  • Prosomeric model - hypothalamus and telencephalon are part of the secondary prosencephalon
• ventro-lateral wall intermediate zone proliferation
• Mamillary bodies - form pea-sized swellings ventral wall of hypothalamus

• Sonic hedgehog (Shh) - initially expressed in prechordal plate, is essential for inductive process.

Diencephalon region, shown by optic stalk (Stage 13)	Late embryonic hypothalamus (Stage 22)

• 

  Human Embryo Brain
  (week 4.5 exterior view)

• 

  Human Embryo Brain
  (week 5 exterior view)

• 

  Human Embryo Brain
  (week 5 interior view)

• 

  Human Fetal Brain
  (3 months)

• 

  Human Fetal Brain
  (4 months)

Hormones - Corticotrophin releasing hormone (CRH), Thyrotrophin releasing hormone (TRH), Arginine vasopressin (AVP), Gonadotrophin releasing hormone (GnRH), Growth hormone releasing hormone (GHRH), Somatostatin, Prolactin relasing factor (PRF), Dopamine

Links: Endocrine - Hypothalamus Development

Pituitary

Blue - neural tube ectoderm Red - surface ectoderm

Dual ectoderm origins Neuroectoderm - prosenecephalon then diencephalon, neurohypophysis Ectoderm - ectoderm roof of stomodeum, Rathke's pouch, adenohypophysis

Adenohypophysis

• Anterior wall proliferates - pars distalis
• Posterior wall little growth – pars intermedia
• Rostral growth around infundibular stem – pars tuberalis

Neurohypophysis

• Infundibulum – median eminence, infundibulum, pars nervosa

Pituitary Timeline

Early Fetal (week 12)

• Week 4 - hypophysial pouch, Rathke’s pouch, diverticulum from roof
• Week 5 - elongation, contacts infundibulum, diverticulum of diencephalon
• Week 6 - connecting stalk between pouch and oral cavity degenerates
• Week 8 - basophilic staining cells appear
• Week 9 - acidophilic staining cells appear
• Week 10 - growth hormone and ACTH detectable
• Week 16 - adenohypophysis fully differentiated and TSH increases to peak at 22 weeks
• Week 20 to 24 - growth hormone levels peak, then decline
• Birth - second TSH surge and decreases postnatally

Links: Endocrine - Pituitary Development | Embryo Images - Pituitary | Endocrinology

Thyroid

Embryo Stage 13 and 22 thyroid (GA week 6 and 10)	Tongue foramen caecum	Thyroglossal duct

• thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum.
• tongue grows, cells descend in neck.
• thyroglossal duct - proximal end at the foramen caecum of tongue.
• thyroid diverticulum - hollow then solid, right and left lobes, central isthmus.

Thyroid Timeline

• GA week 6 - thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum (FA 24 days)
• GA week 13 - colloid appearance in thyroid follicles, iodine and thyroid hormone (TH) synthesis. Growth factors (insulin-like, epidermal) stimulates follicular growth.
  • Fetal TH - initial secreted biologically inactivated by modification
• GA 18-20 weeks - fully functional
  • late fetal secretion develops brown fat
• Birth - TSH levels increase, thyroxine (T3) and T4 levels increase to 24 h, then 5-7 days postnatal decline to normal levels.

Maternal TH - iodine/thyroid status can affect development.

• studies show that both high and low maternal thyroid hormone can impact on neural development )
• Iodine deficiency - during prenatal period, leads to low fetal TH and neurological defects (cretinism).

Human thyroid system and neural development

Parathyroid - different embryonic origin

• Endoderm - third and fourth pharyngeal pouches, could also have ectoderm and neural crest
  • 3rd Pharyngeal Pouch - inferior parathyroid, initially descends with thymus
  • 4th Pharyngeal Pouch - superior parathyroid

Links: Thyroid | Endocrine - Parathyroid Development|Parathyroid | Endocrinology |

References

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Cite this page: Hill, M.A. (2024, June 3) Embryology Royal Hospital for Women - Reproductive Medicine Seminar 2018. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Royal_Hospital_for_Women_-_Reproductive_Medicine_Seminar_2018

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© Dr Mark Hill 2024, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G