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INTRODUCTION TO EMBRYOLOGY Assoc Prof Dr E.Elif GÜZEL Definition of Embryology • The study of the developmental process from a single cell to a baby in 9 months. • In other words, investigations of the molecular, cellular and structural factors contributing to the formation of an organism. Human Development • • • • Development does not stop at birth!! How does it start? Zygote (totipotent cell) Human Transformation mechanisms include: – – – – – – cell division, cell migration, apoptosis, differentiation, growth, cell rearrangement Clinical Importance • Understanding embryology is essential for creating health care strategies; 1. 2. 3. Prenatal diagnosis and surgical treatments Therapeutic procedures for infertility Mechanisms to prevent birth defects Improvements in prenatal and reproductive health is significant for improved birth outcomes postnatal long-term effects prenatal experiences effects cognitive capacity and postnatal health IMPOTANT FOR MOST PHYSICIANS • Embryogenesis (organogenesis); – Establishment of the organ primordia from a single cell – The first 8 weeks of human development • Fetal period; – From 9th week to birth – Differentiation and growth – Fetus gains weight • Trimester; – 1/3 of the normal length of pregnancy • Teratology; – Study of the embryological causes for birth defects • Genetic • Environmental Descriptive Terms in Embryology • Spermatozoon= Sperm • According to the anatomical position, the position of the organs are described using some terms: – – – – Anterior/ventral Posterior/dorsal Superior/ cranial (or rostral) Inferior/caudal Molecular Regulation of Embryogenesis • Progress in the field of molecular biology enhanced our understanding of normal and abnormal development • 23,000 genes…..150,000 proteins Chromatin • Chromatin: a complex of DNA and histone proteins • Nucleosome: the basic structural unit of chromatin • Nucleosomes keep the DNA tightly coiled, such that it cannot be transcribed….heterochromatin • DNA must be uncoiled to be transcribed…. euchromatin Gene Transcription Regulation of Gene Expression **Transcription Factors • Protein that binds to specific DNA sequences, and control the transcription of genetic information from DNA to mRNA. • Depending on the transcription factor, the transcription of the adjacent gene is either activated or inhibited. **DNA Methylation • Methylation of cytosine bases in the promoter regions of genes inhibits transcription of those genes. • Some genes are silenced by this mechanism – Muscle cells make muscle proteins not blood proteins **Alternative Splicing • Why different cells by using the same gene produce different proteins?? A single gene may give rise to several proteins • By removing different introns from pre-mRNA • Splicing isoforms Post-translational Modifications • Activation of some proteins depends on…. – Combination with other proteins – Phosphorylation – Cleavage Induction and Organ Formation • How does organ formation occur??? Organs are formed by interactions between cells and tissues One group of cells or tissues causes another set of cells or tissues to change their fate INDUCTION Inducer-Cell Signaling-Responder Inductive Interactions Between Epithelial and Mesenchymal Cells • Epithelial cells join together to form tubes or sheets • Mesenchymal cells are fibroblastic in appearance and dispersed in extracellular matrix • Although an initial signal from inducer to responder starts the inductive event, crosstalk between two tissues or cell types is essential for differentiation to continue Examples of Epithelial-Mesenchymal Interactions • Gut endoderm and surrounding mesenchyme…. gut derived organs (liver, pancreas) • Development of the kidney Cell Signaling • Essential for induction • Established by signaling proteins (ligand) • Receptor – Spans the cell membrane • Extracellular domain (ligand binding region) • Transmembrane domain • Cytoplasmic domain • Action??? – Activating directly – Blocking the activity of an inhibitor of a pathway (inhibiting an inhibitor) Typical Signal Transduction Pathway Process 1. 2. 3. 4. 5. 6. Ligand binds its receptor….. Conformational change occurs in the receptor…. Cytoplasmic region gains an enzymatic activity (mostly kinase)…. Phosphorylation of some cytoplasmic proteins…. Activation of a transcription factor…. Activation or inhibition of genes. Types of Signal Transduction Pathways • Paracrine Signaling; proteins synthesized by one cell diffuse short distances to interact with other cells • Juxtacrine Signaling; does not involve diffusable proteins Paracrine Signaling • Diffusable proteins responsible for the paracrine signaling are called paracrine factors or growth and differentiation factors (GDFs). • Uses typical signal transduction pathway process. Juxtacrine Signaling 1. A protein on one cell surface interacts with a receptor on an adjacent cell uses typical signal transduction pathway process Notch signaling (neuronal and blood vessel differentiation, somite segmentation) 2. Ligands in the extracellular matrix interact with their receptors on neighboring cells (cells attach to or migrate on these ligands) Epithelial cells attach to laminin of basal lamina Fibronectin for cell migration Receptors are called integrins 3. Gap junctions Paracrine Signaling Factors (GDFs) • Regulate development and differentiation of organ systems • Grouped into 4 families; – – – – Fibroblast growth factor WNT Hedgehog Transforming growth factor-β (TGF-β ) Fibroblast Growth Factors (FGFs) • Originally named because they stimulate the growth of fibroblasts in culture • app. 25 different genes….hundreds of proteins • Receptor tyrosine kinases (FGFRs) • Important for; – angiogenesis – axon growth – mesoderm differentiation • e.g. FGF8 is important for development of the limbs and part of the brain Hedgehog Proteins • There are 3 hedgehog genes; – Desert – Indian – Sonic hedgehog • Sonic Hedgehog is important in – – – – Limb patterning Neural tube induction or patterning Somite differentiation Gut regionalization • Action on the receptor is inhibiting an inhibitor WNT Proteins • Involved in regulating…. – limb patterning – midbrain development – somite differentiation – urogenital differentiation TGF-β Superfamily • More than 30 members – TGF-βs • Important for extracellular matrix formation • Important for epithelial branching that occurs in the lung, kidney and salivary gland development – Bone morphogenetic proteins (BMPs) • Induces bone formation • Regulates cell division, apoptosis, cell migration – Activin familiy – Müllerian inhibiting factor Other Paracrine Signaling Molecules • Two neurotransmitters important for embryological development • Seratonin (5HT) – – – – – Cell proliferation Cell migration Establishing laterality Gastrulation Heart development • Norepinephrine – Apoptosis in interdigital spaces References 1. 2. The Developing Human: Clinically Oriented Embryology by Keith L. Moore, T. V. N. Persaud and Mark G. Torchia (2013). 9th ed. Elsevier Saunders, Philadelphia. ISBN: 978-0-8089-2444-9 Langman’s Medical Embryology by T.W. Sadler (2012). 12th ed. Lippincott Williams & Wilkins, Philadelphia. ISBN: 978-1-4511-4461-1