Embryonic Development (1).pdf

Embryology I Embryonic Genes 4 genes Development body pattern: Head, arms, legs o Sonic Hedgehog (SHH) o Fibroblast Growth Factor (FGF) o Wnt-7a o Homeobox gene (HOX) Sonic Hedgehog Gene (SHH) Makes SHH protein An embryonic signaling protein Embryonic roles: Limbs, Brain, Eyes Key roles: CNS and Lim...

Embryology I Embryonic Genes 4 genes Development body pattern: Head, arms, legs o Sonic Hedgehog (SHH) o Fibroblast Growth Factor (FGF) o Wnt-7a o Homeobox gene (HOX) Sonic Hedgehog Gene (SHH) Makes SHH protein An embryonic signaling protein Embryonic roles: Limbs, Brain, Eyes Key roles: CNS and Limb (anterior posterior) o CNS development § Formation of forebrain § Signaling separates R and L brain § Establishes midline § Develops through enlargement of neural tube vesicles — Primary Vesicle = 3 regions @ 3-4wks o Prosencephalon (forebrain) o Mesencephalon (midbrain) o Rhombencephalon (hindbrain) — Secondary Vesicle = 5 regions @ 5wks o Telencephalon o Diencephalon o Mesencephalon o Metencephalon o Myelencephalon § Holoprosencephaly mutation — SHH mutation — Failed division of prosencephalon (forebrain) into double lobes of the cerebral hemispheres — Single-lobed brain — No L/R hemispheres — Facial abnormalities (Cleft lip/palate, Cyclopia) o Limb anterior posterior development § Limb patterning § Limb development along 3 planes: — Proximal to distal (Humerus - radius - wrist) — Dorsal-ventral axis — Anterior-posterior (AP) axis Summary of Embryonic Genes SHH o CNS development and limb o AP limb axis patterning o Mutations: Holoprosencephaly FGF o Produced at limb bud à proximal-distal limb outgrowth Wnt-7a o Produced at limb bud à dorsal-ventral limb axis patterning Homeobox (Hox) gene o Produced at multiple locations à AP axis patterning o Mutations – abnormal digits/toes Fibroblast Growth Factor FGF Gene Transcription factor Produced at limb bud Proximal-distal limb outgrowth o (Humerus -> radius -> wrist) Wnt-7a Produced at limb bud Early embryo o Important for limb dorsal-ventral development Later embryogenesis o Development of the anterior-posterior axis in female reproductive tract Homeobox Genes (HOX) Code for transcription factors Produced at multiple locations Regulators of limb AP axis development Family of genes: HOXA1, HOXB1, HOXD1, etc Mutation à Limb malformations o Polydactyly (extra fingers/toes) o Syndactyly (fused fingers/toes) Embryonic Development Fertilization is the union of an egg and sperm occurs in the ampulla of the fallopian tube 1N, 1C: Haploid mature spermatozoon N = # of chromosomes 1N, 1C: Haploid ovum 2N, 2C: zygote C = # of chromatids (DNA copies) DNA Synthesis Pronucleus contains Maternal/paternal DNA. This genetic material is not yet united This material has not yet split 2N, 2C à DNA synthesis à Chromatids à 2N, 4C Zygote divides into two cells (2N, 2C) Cleavage Zygote divides into 2 cells o Mitosis continues and first 2 cells divide into 4, then 8… o Division takes 12-24hrs Fetal Development: Two-Cell stage: first 1-2 days AFTER fertilization Morula “ball of cells”: Cells continue to divide Blastulation Formation of blastula from morula Blastula contains fluid cavity called blastocoel In humans, blastula called blastocyst o Outer cells: trophoblast § Polarized: one side different from other § Watery fluid of blastocoel secreted by trophoblast cells o Inner cell mass (apolar) § Give rise to all tissues of body § Embryonic stem cells derived from inner cell mass Implantation Blastocyst implants in uterus at day 6-10 β-hCG secretion begins (Beta Human Chorionic Gonadotropin) Early Embryonic Development Fertilization occurs in ampulla of uterine tube (union of an egg and sperm) Fertilized egg (zygote), initiates embryonic development Implantation occurs around day 6 o Blastocyst “sticks” around day six o hCG secretion begins, maintaining corpus luteum - Sperm enters, sheds acrosomal head when penetrating zona pellucida - Egg will be fertilized - Ovulated mammalian oocyte is arrested at metaphase of meiosis II Gastrulation Blastula (single-layered hollow sphere of cells) is reorganized into a two-three-layered embryo known as the gastrula Bilaminar germ disc forms in week 2 (Inner cell mass à bilaminar disc) Two cell layers separated by the basement membrane o Epiblast and hypoblast o Epiblast: gives rise to 3 layers of gastrulation (ecto, meso, endo) o Hypoblast: gives rise to Yolk sac Primitive Streak Formed by invagination of epiblast cells Creates a visible line (“streak”) in blastocyst Presence indicates start of gastrulation During Gastrulation, three germ layers of embryos (ectoderm, mesoderm, and endoderm) develop, giving rise to different organ systems Trilaminar germ disc forms in week 3 o 1. Ectoderm – external layer o 2. Mesoderm – middle layer o 3. Endoderm – internal layer Ectoderm also develops the Neural tube (CNS) and Neural Crest (PNS) Embryonic Period First 8 weeks AFTER fertilization o Organogenesis occurs o Vulnerable period to tetragons o Followed by fetal established § Most adult structure established § Organs/structure grow Heart Development o Week 4 – Heart begins beating (four chambers) o Week 6 – Transvaginal ultrasound detects fetal heart movement Limbs o Week 4 – Upper and lower limb buds begin to form (four limbs) o Week 8 – Baby begins moving Genitalia o Week 8 § Genitalia looks similar for males and females § Sex-determining region Y (SRY gene) – penis development § Lack of SRY gene – clitoris development o Week 15 to 20: Ultrasound will identify gender. Pituitary Gland Anterior pituitary (adenohypophysis) o From Rathke’s pouch of ectoderm o Outpouching of upper mouth Posterior pituitary (neurohypophysis) o Rise from neural tube Adrenal Gland Cortex: Mesoderm à Aldosterone, cortisol, androgens Medulla: Neural crest à Epinephrine, norepinephrine Summary Week 1 o hCG secretion begins around the time of blastocyst implantation o Blastocyst “sticks” on day 6 Week 2 o Formation of bilaminar embryonic disc; two layers = epiblast, hypoblast Week 3 o Formation of trilaminar embryonic disc via gastrulation; three layers = endoderm, mesoderm, ectoderm § 1. Ectoderm – external layer (Skin, Nervous system) § 2. Mesoderm – middle layer (Muscle, skeleton, kidney, heart, blood, reproductive system) § 3. Endoderm – internal layer (Digestive tract, liver, lungs, thyroid) Week 4 o The heart begins to beat (four chambers) o Upper and lower limb buds begin to form (four limbs) Week 8 o Genitalia has male/female characteristics Which of the following is NOT derived from endoderm? a) Liver b) Pancreas c) Thymus d) Heart d Error in Morphogenesis Intrinsic o Failure of embryo to develop o Abnormal gene or other internal processes o Agenesis, aplasia, hypoplasia, malformation Extrinsic o External forces impact normal development o Disruption and deformation Causes of morphogenesis error Genetic o Chromosomal aberrations 10-15% o Mendelian Inheritance 2-10% Environmental o Maternal/placental infections 2–3% o Maternal disease states 6-8% o Drugs and chemicals 1% Multifactorial 20-25% Unknown 40-60% Intrinsic Errors Agenesis: Organ missing due to missing embryonic tissue (ex. Renal agenesis: failure of one or both kidneys to develop) Aplasia: Organ missing due to growth failure of embryonic tissue (ex. Thymic aplasia -DiGeorge Syndrome) Hypoplasia: Incomplete organ development (ex. Microcephaly) Malformation: Abnormal development of structure (ex. Cleft lip/palate, Congenital heart defect) Extrinsic Errors Disruption o Normal tissue growth arrested due to external force o Amniotic band syndrome § Occurs when loose bands of tissue in the uterus entangle a developing fetus § Bands can restrict blood flow, affecting the growth of certain body parts § Often involves limbs or digits Deformation o External force leads to abnormal growth o Deforms or misshapes structure o Potter’s syndrome (Potter’s sequence) § Abnormal development of the kidneys § Fetus exposed to low/absent amnionic fluid § Loss of fetal cushioning to external force § External compression of fetus: Abnormal face/limb formation § Alteration in lung liquid content: Abnormal lung formation Summary Intrinsic Errors: Agenesis- Missing organ caused by missing embryonic tissue Aplasia - Missing organ due to growth failure of embryonic tissue Hypoplasia - Incomplete organ development Malformation - Abnormal development of structure Extrinsic Errors: Disruption- Normal tissue growth arrested due to external force Deformation- External force leads to abnormal growth Teratogens Substances that cause abnormal fetal development Common effects: o Fetal loss o Growth restriction o Birth defects o Impaired neurological function Teratogen Timing Greatest risk for fetal exposure in 1st trimester o Embryonic period o Formation of organs Week 2-8 o Organogenesis o Structural defects After week 8 o Fetal period (growth and function) o Decreased growth o CNS dysfunction o Usually, no birth defects Teratogen Substances Drugs Substance abuse (Alcohol, cocaine, smoking) Radiation Chemicals (Mercury) Maternal illness (Diabetes) Infectious agents (Rubella, CMV, Herpes) FDA Labels for Drugs During Pregnancy Category Interpretation A B C D X ACE Inhibitors and ARBs Pregnancy D 1st trimester: congenital malformation 2nd 3rd trimester: Oligohydramnios (deficiency of amniotic fluid) o Neural tube defects o Fetal kidney function decreased o Fetal renal failure o Can lead to Potter’s syndrome o Pulmonary hypoplasia, limb/skeletal deformities Methimazole Treatment for hyperthyroidism Pregnancy D May cause fetal and neonatal hypothyroidism Aplasia cutis: absence of epidermis on scalp o Solitary defect on scalp o Missing patch skin/hair Propylthiouracil used in 1st trimester Chemotherapy Fetal malformation 15% with therapy in 1st trimester Ideally chemotherapy is deferred o After birth o 2nd/ 3rd trimester Highest risk: alkylating agents and anti-metabolites o Spontaneous abortion o Missing digits o Many other fetal abnormalities Vitamin A Excess Teratogenic in the first trimester Spontaneous abortions Microcephaly Cardiac abnormalities No risk to fetus Maybe acceptable; no risk to fetus Use w caution, animal studies show risk Positive evidence of risk (ACEI, ARB, methimazole, warfarin) Contraindicated in pregnancy (5 alpha reductase, Isotretinoin) 5 alpha Reductase Inhibitors Dihydrotestosterone (DHT) blockers Used for enlarged prostate and scalp hair loss Pregnancy X: Failure of genital develop in male fetus Propecia, Proscar, Avodart: Do not use if you are female Seizure Drugs All seizure drugs may affect a fetus Many of them are associated with folic acid o Neural tube defects o Congenital heart disease o Cleft palate o Short fingers o Abnormal facial features High-risk drugs o Valproic acid (neural tube defects) o Phenobarbital o Carbamazepine Folic acid supplementation needed in high dose Isotretinoin Derivative of Vitamin A Used to treat acne Pregnancy X o Spontaneous abortion 20% o Abnormal facial features o Congenital heart disease o Hydrocephalus Birth control mandatory Antibiotics Aminoglycosides o Reports of permanent deafness in fetus Tetracycline o Accumulates in fetal teeth and long bones o May permanently discolor fetal teeth Alcohol Neurotoxin May cause fetal alcohol syndrome o Congenital heart defects o Skeletal anomalies o Intellectual disability o Characteristic facial features First trimester o Facial abnormalities o Brain abnormalities o Congenital heart disease Third trimester o Mostly affects the size of the baby, brain growth o Intellectual impairment Cocaine Vasoconstriction Low birth weight Placental abruption Preterm birth Miscarriage X-Rays No evidence of harm at small doses High dosages at 8-15 weeks cause: o Intellectual disability o Microcephaly o Growth restriction Lead shielding use to protect fetus Warfarin Anticoagulant Pregnancy class D Fetal hemorrhage, spontaneous abortion Optic atrophy (vision loss) Use heparin during pregnancy (does not cross the placenta) Warfarin Embryopathy o Bone and cartilage abnormalities o Stippled epiphyses: small, round densities on X-ray o Nasal hypoplasia o Limb hypoplasia Smoking Toxins: Nicotine and carbon monoxide Impaired oxygen delivery to the fetus Nicotine induces vasoconstriction – reduced placental blood flow Carbon monoxide impairs O2 delivery – reduced oxyhemoglobin Risk o Low birthweight o Placental anomalies o Preterm labor o Sudden infant death syndrome Mercury Methylmercury found in fish/seafood o Not removed by cooking o Highest levels: swordfish, shark, tilefish, Mackerel King Fetal brain is highly sensitive to mercury Mothers not usually affected Delayed milestones Rarely blindness, deafness, or cerebral palsy Maternal Diabetes Multiple effects on fetus: o Macrosomia (large baby, babies often >9lbs at birth) o Blood sugar alterations (neonatal hypoglycemia) o Congenital Heart Disease (Transposition of the great artery, VSD) o CNS disorders Adverse effects related to severity of diabetes Summary: Teratogens Before week 8 (embryonic period): formation of organs After week 8 (fetal period): growth and function Medications: o ACEI o Antiepileptic drugs o Chemotherapy o Isotretinoin o Vitamin A o Tetracyclines o Warfarin Substance Use: Alcohol Cocaine Tobacco smoking Other: Methylmercury Neurotoxicity X-rays Maternal diabetes