Embryology and congenital anomalies Yasser Orief M.D. Lecturer of Obstetrics & Gynecology, Alexandria University Fellow, Lϋbeck University, Germany DGOL, Auvergné University, France

Embryology – study of the origin and development of single individual Prenatal period Embryonic period – first 8 weeks Fetal period – remaining 30 weeks

Embryonic Period

Fetal Period

The Basic Body Plan Skin – dermis and epidermis Outer body wall – trunk muscles, ribs, vertebrae Body cavity and digestive tube (inner tube) Kidneys and gonads – deep to body wall Limbs

The Basic Body Plan

Week 1 – from zygote to blastocyst The Embryonic Period Week 1 – from zygote to blastocyst Conception – in lateral third of uterine tube Zygote (fertilized oocyte) moves toward the uterus Blastomeres – daughter cells formed from zygote Morula – solid cluster of 12–16 blastomeres “Mulberry” Blastocyst – fluid-filled structure – ~ 60 cells

The Embryonic Period Stages of first week Zygote 4-cell Morula Early blastocyst Late blastocyst (implants at this stage)

Fertilization and the Events of the First 6 Days of Development

Week 2 – The Two-Layered Embryo Bilaminar embryonic disc – inner cell mass divided into two sheets Epiblast and the hypoblast Together they make up the bilaminar embryonic disc

Week 2 – The Two-Layered Embryo Amniotic sac – formed by an extension of epiblast Outer membrane forms the amnion Inner membrane forms the amniotic sac cavity Filled with amniotic fluid

Week 2 – The Two-Layered Embryo Yolk sac – formed by an extension of hypoblast Digestive tube forms from yolk sac NOT a major source of nutrients for embryo Tissues around yolk sac Gives rise to earliest blood cells and blood vessels

Implantation of the Blastocyst

Implantation of the Blastocyst

Implantation of the Blastocyst

Week 3 – The Three-Layered Embryo Primitive streak – raised groove on the dorsal surface of the epiblast Gastrulation – a process of invagination of epiblast cells Begins at the primitive streak Forms the three primary germ layers

Week 3 – The Three-Layered Embryo Three Germ Layers* Endoderm – formed from migrating cells that replace the hypoblast Mesoderm – formed between epiblast and endoderm Ectoderm – formed from epiblast cells that stay on dorsal surface *All layers derive from epiblast cells!

The Primitive Streak

Primitive node – a swelling at one end of primitive streak The Notochord Primitive node – a swelling at one end of primitive streak Notochord forms from primitive node and endoderm Notochord – defines body axis Is the site of the future vertebral column Appears on day 16

Formation of the Mesoderm and Notochord

Neurulation – ectoderm starts forming brain and spinal cord Neural plate – ectoderm in the dorsal midline thickens Neural groove – ectoderm folds inward

Neurulation (continued) Neural tube – a hollow tube pinches off into the body Cranial part of the neural tube becomes the brain Maternal folic acid deficiency causes neural tube defects

Neurulation Neural crest Induction Cells originate from ectodermal cells Forms sensory nerve cells Induction Ability of one group of cells to influence developmental direction of other cells

The Mesoderm Begins to Differentiate Somites – our first body segments Paraxial mesoderm Intermediate mesoderm – begins as a continuous strip of tissue just lateral to the paraxial mesoderm

The Mesoderm Begins to Differentiate Lateral plate – most lateral part of the mesoderm Coelom – becomes serous body cavities Somatic mesoderm – apposed to the ectoderm Splanchnic mesoderm – apposed to the endoderm

Changes in the Embryo

Changes in the Embryo

Week 4 – The Body Takes Shape Folding of embryo laterally and at the head and tail Embryonic disc bulges; growing faster than yolk sac “Tadpole shape” by day 24 after conception Primitive gut – encloses tubular part of the yolk sac Site of future digestive tube and respiratory structures

Week 4 – The Body Takes Shape

Week 4 – The Body Takes Shape Derivatives of the germ layers Ectoderm forms Brain, spinal cord, and epidermis Endoderm forms Inner epithelial lining of the gut tube Respiratory tubes, digestive organs, and urinary bladder Notochord – gives rise to nucleus pulposus within intervertebral discs

Week 4 – The Body Takes Shape Mesoderm – forms Muscle Bone Dermis Connective tissues (all) Mesoderm differentiates further and is more complex than the other two layers

Week 4 – The Body Takes Shape Mesoderm (continued) Somites divides into Sclerotome Dermatome Myotome Intermediate mesoderm forms Kidneys and gonads

Week 4 – The Body Takes Shape Mesoderm (continued) Splanchnic mesoderm Forms musculature, connective tissues, and serosa of the digestive and respiratory structures Forms heart and most blood vessels Somatic mesoderm – forms Dermis of skin Bones Ligaments

Derivatives of Germ Layers

The Germ Layers in Week Four

Week 5-8 – The Second Month of Embryonic Development Limb buds form Embryo first looks recognizably human (week 8) Head is disproportionately large All major organs are in place

The Fetal Period A time of maturation and rapid growth Cells are differentiating during the first half of the fetal period Normal births occur 38 weeks after conception Premature birth is one that occurs before 38 weeks

Developmental Events of the Fetal Period

Developmental Events of the Fetal Period

Developmental Events of the Fetal Period

SEX DETIRMINATION

Sex determination Sex determination in human is genetically controlled. TDF (testis determining factor ) is a dominant gene on the Y chromosome. Presence of this gene will lead to testicular formation. In the absence of this gene the default sex is female.

The newly formed embryonic testis will secrete Mullerian inhibitory factor (MIF) from Sertoli cells: It causes regression of the mullerian ducts. Regression of any germ cells that developed into oogonia. Testosterone from the Leyding cells: Differentiation and growth of the wollfian duct structures. Masculinization of the external genitalia after conversion to DHT.

In the absence of signals from TDF: sertoli cell differentiation does not occur. Migrating germ cells differentiate as oogonia. Interstitial cells differentiate as granulosa cells. sex differentiation of germ cells is determined, not only by their genetic constitution, but also by their tissue environment.

In the absence of testosterone In the absence of MIF : Mullerian ducts differentiate and grow as female internal genitalia. In the absence of testosterone External genitalia are feminized.

PGCs on to ridge by week 6 First hint of gonad in week 4 but remain indifferent (or bipotential) until week 7. Only then can the type of gonad be distinguuished

So what does Y have to do with it in humans?

There is also a set of reproduction-specific (Rhox) homeobox genes expressed In males one set in Sertoli cells, other set in Leydig cells All genes are on the X chromosome Are under androgen regulation The Sertoli set is sequentially expressed and thought to provide mechanism by which Sertoli cells regulate germ cell devliopment (proliferate->devide-> differentiate)

From: Wolpert et al., Principles of Development

From: Gilbert, Developmental Biology

From: Gilbert, Developmental Biology

From: Wolpert et al., Principles of Development

From: Gilbert, Developmental Biology

From: Larsen, Human Embryology Should take time to get familiar with other major defects seen in external genital system (e.g. uterine anomalies, cryptorchidism) From: Larsen, Human Embryology

Type I Agenesis uterine, or uterine hypoplasia Type II Uterus unicornuate Type III Uterus didelphys Type IV Uterus bicornuate (including arcuate uterus) Type V Uterus septate Type VI Uterine anomaly associated with DES exposure

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