Developmental Genetics and Birth

Defects
Ramona Dumitrescu
r.dumitrescu@saba.edu
Saba University Medical School
Spring 2014

Outline

Developmental Biology in Medicine
Development and Evolution
Genes and Environment in Development
Concepts in Developmental Biology
Cellular and Molecular Mechanisms in
Development

Developmental Biology in Medicine
20% of infants deaths – attributable to birth defects
Another 20% of infants death – complications of
prematurity (=failure to maintain the maternal-fetal
developmental environment)
Clinical dysmorphology = study of congenital birth
defects that alter the form or shape of one or more
parts of the body of a newborn child
-tries to understand the genetic and environmental
contribution to the birth defects
-objectives: to diagnose the defects, suggest
evaluations, give prognostic info, develop
management plans, give recurrence risks

Birth defects

3 categories:
 Malformations
 Deformations
 Disruptions

Greig cephalopolysyndactyly -loss-of-function mutation in GLI3 gene -GLI3 part of a complex of molecules – that cause the development of distal end of the human upper limb bud into a hand with 5 digits Polydactyly and syndactyly malformations . Malformations results from intrinsic abnormalities in one or more genetic programs involved in development e.g.

Deformations Caused by extrinsic factors impinging physically on the fetus during development Common during the second trimester of development e. Arthrogryposes (constraint of the joints of the extremities) and deformation of the developing skull – due to constraint of the fetus because of twin or triplet pregnancy or prolonged leakage of amniotic fluid .g.

g. Disruptions Result from destruction of irreplaceable normal fetal tissue because of vascular insufficiency. Amnion disruption (=partial amputation of a fetal limb associated with strands of amniotic tissue) -presence of partial and irregular digit amputations in conjunction with constriction rings . trauma or teratogens e.

radiation . chemicals. Causes of malformations Chromosomal imbalance: trisomies 21. infections. congenital heart defects Teratogens exposures: drugs. 18 and 13 Mutations in single-gene: -autosomal dominant: achondroplasia -X-linked recessive : Lowe syndrome complex inheritance: cleft lip with or without cleft palate.

branchio-oto-renal dysplasia syndrome -abnormal cochlear and external ear development -cysts and fistulas in the neck -renal dysplasia -renal duct abnormalities -caused by mutations in EYA1 gene –encodes for a protein phosphatase with functions in both ear and kidney .g. Pleiotropy =when a single underlying causative agent results in abnormalities of more than one organ system or in multiple structures that arise at different times during intrauterine life Agent causing multiple abnormalities in parallel =syndrome Mutant gene or teratogen affects only a single organ system =sequence E.

g. Rubenstein-Taybi syndrome -caused by loss of function in a transcriptional coactivator - abnormalities in transcription of many genes -mental retardation -broad thumbs and large toes -distinctive facial appearance -congenital heart defects . Pleiotropy E.

g. defects in stature. Pleiotropy E. joints . Robin sequence (U-shape cleft palate and small mandible) -restriction of mandibular growth before the ninth week of gestation -tongue lies more posteriorly than is normal. interfering with normal closure of palatal shelves – cleft palate -can be observed in Stickler syndrome – mutations in the gene encoding for type II collagen results in an abnormally small mandible.

seal. Development and Evolution Homologous structure = structure in different organisms that evolved from a structure present in a common ancestor Diagram of the upper limb of four species: Human. bird and bat .

Development and Evolution Analogous structure = structure that appear similar but they evolve independently of one another E. wing structure of the bats and birds = convergent evolution -birds developed posterior extensions from the limb -bats evolved wings from spreading the digits of their forelimbs and connecting them with syndactylous tissue .g.

Loss of function of murine Pax6 – small eyes C. Misexpression of eyeless in tissue fated to become antenna – normal but misplaced eye . Developmental Genetics Pathways that control development – highly conserved among animal species Studies of non-human models – critical in understanding human development and the causes of birth defects A. Mutations in human PAX6 – aplasia of the irides B.

Genes and environment in development .

differentiation and apoptosis – result with a high degree of probability in correct mature structures . migration. Developmental Genetics Development = from the action of genes interacting with cellular and environmental cues Most of the developmental disorders –caused by genome. chromosome. gene mutations Genome specifies a set of interacting proteins and noncoding RNAs – growth.

Drug used for acne – mimics the action of endogenous retinoic acid (important in developing embryo and fetus –diffuses through tissues and interacts with cells – follow particular development pathways) E. Environmental factors Teratogens= cause birth defects Explanation – teratogens may affect the cellular and molecular pathways used during development (unique and not employed after adulthood) E.g. thalidomide syndrome -sedative used in the 1950 -caused high incidence of malformed limbs in fetuses exposed between 4 and 8 weeks of gestation .g fetal retinoid syndrome -in fetuses of pregnant women who took the drug isotretinoin (vitamin A creams?) during pregnancy .

Concepts in Developmental Biology .

Cellular processes during development Cells during development  Proliferate  Differentiate  Migrate  Undergo apoptosis To allow growth and morphogenesis Congenital segmental overgrowth -small part of the body –few toes .

inside the cells will make the embryo itself aggregate to one side = inner cell mass . Human embryogenesis Human development begins with fertilization -single fertilized egg undergo 4 divisions – 16 cell morula -embryo becomes a blastocyst – cells that give rise to the placenta form a wall.

Human embryogenesis Inner cell mass separates into the epiblast (will make the embryo) and hypoblast (make the amniotic membrane) .

kidneys. heart. Mesoderm . organogenesis Weeks 9-40 – fetal phase . Ectoderm – central and peripheral nervous systems and the skin 2. Human embryogenesis The embryo implants in the endometrial wall of the uterus between 7-12 days after fertilization Gastrulation occurs – cells rearrange themselves – structure with 3 cellular compartments 1. bones and muscles 3. vasculature. Endoderm – central visceral core of the organism (gut cavity. establishment of the body plan. the airways of the respiratory system) Weeks 4-8 – initiation of the nervous system.

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Stem Cells: Maintaining Regenerative Capacity Organism must set aside tissue specific stem cells to regenerate differentiated cells in the adult life E.g. hematopoietic system -104 – 105 cells –have the potential to generate any specialized blood cells continuously during a lifetime -there is a balance between self-replication and generation of committed precursor cells .

g nerve cells make synaptic proteins but not hemoglobin . Fate. Specification and Determination Fate = process of differentiation that include several steps in which the cells manifest various functions or attributes before reaching the final destination Specification = acquiring specific characteristics early during differentiation. characteristics that can be modified by environmental factors Determination = irreversible acquisition of specific attributes E.

g.early in development – removal or ablation of part of an embryo can be compensated for by the remaining similar cells E. Regulative and Mosaic Development Regulative development . monozygotic twins – early development is regulative – second half of first week of development Mosaic development – later in development – loss of a portion of an embryo would lead to the failure development of structures that had a specific fate .

conjoined twins .g. Regulative and Mosaic Development Regulative development: E. preimplantation diagnosis – early development is regulative Mosaic development: E.g.two fetuses share body structures and organs because cleavage occurred after the transition from regulative to mosaic development .

Axis Specification and Pattern Formation .

g. Axis Specification Cranial-caudal axis –established very early in embryogenesis. Sonic hedgehog) – participate in setting up the axis of dorsal-ventral polarity Left-right axis – essential for proper heart development and positioning of viscera (abnormality of ZIC3 gene – situs inversus) . probably determined by the entry position of the sperm that fertilizes the egg Dorsal-ventral axis – interacting proteins and signaling pathways (e.

Axis Specification .

different number of HOX genes – 8 in the fruit flies and 40 in humans (clusters A. C and D) . Pattern Formation Patterning = division of the embryo into segments and the assignment of an identity (head. thorax. abdomen etc) Homeobox (HOX) gene system -first discovered in Drosophila melanogaster -encode transcriptional factors containing a conserved DNA-binding domain =homeodomain -many species .B.

HOX gene system 4 clusters: HOXA. HOXB. HOXC and HOXD Unique combination of HOX gene expression in a small groups of cells in specific regions in the embryo – developmental fate of these regions Early in development – HOX transcription factors specify the anterior-posterior axis (HOXA and HOXB clusters) Later in development – HOXA and HOXD clusters - determine regional identity along the axes of the developing limb .

HOX gene system -Summary A group of genes functions together to accomplish similar general tasks at different times and places in the embryo Homologous structures generated by sets of transcription factors derived from common evolutionary predecessor Show a genomic organization within a cluster that correlates with their function during development (the position of a HOX gene in a cluster is co-linear with both the timing of expression and the location of expression along the anterior-posterior axis in the embryo) .

Cellular and molecular mechanisms in development .

Mechanisms Involved in Development Gene regulation by transcription factors Cell-cell signaling by direct contact and by morphogens Induction of cell shape and polarity Cell movement Programmed cell death .

Gene Regulation by Transcription Factors Groups of transcription factors that function together =transcriptional regulatory modules Transcriptional regulatory complex =general transcription factors and specific transcription factors .

feet and ankles -there is an expansion of a polyalanine tract in the amino-terminal domain of the protein (22-24 instead of 15) . Gene Regulation by Transcription Factors Mutation in HOXD13 gene –causes synpolydactyly -heterozygotes have interphalangeal webbing and extra digits in their hands and feet -homozygotes have similar abnormalities and also have bone malformations of the hands. wrists.

fibroblast growth factors (23 members of fibroblast growth factor gene family) and their receptors – abnormalities of the receptors – achondroplasia Developmental morphogen – hedgehog -originally discovered in Drosophilla -in humans –Sonic hedgehog (SHH) -has the ability to alter the orientation of epidermal bristles . Morphogens and Cell-to-Cell signaling Cells communicate with each other to develop proper spatial arrangements of tissues – through cell signaling mechanisms cell-cell communication systems – cell surface receptor and the ligand E.g.

Fibroblast Growth Factor (FGF) family Widely expressed in developing bones Many human autosomal dominant disorders of bone growth – mutations in FGFR3 gene .

Sonic Hedgehog (SHH) Secretion of the SHH protein by the notochord and the floor plate of the developing neural tube generates a gradient that induces and organizes different types of cells and tissues – developing brain and spinal cord SHH is also produced by a small group of cells in the limb bud  zone of polarizing activity – asymetrical pattern of digits with individual limbs .

microcepahly. abnormal brain development -variable expressivity . hypotelorism. Sonic Hedgehog (SHH) Mutations in SHH gene -holoprosencephaly – cleft lip and palate.

Sonic Hedgehog (SHH) Receptor for SHH – protein encoded by patched gene mutations human PATCHED (PTCH) – Gorlin syndrome . cysts of the jaw.rib anomalies. basal cell carcinoma .

muscle. gonads. integrated In humans – 19 Wnt genes – involved in specification of the dorsal/ventral axis and formation of the brain. kidneys Homozygotes for the mutations in WNT3 –tetra- amelia (absence of the four limbs in humans) Abnormal Wnt signaling – tumor formation . Wnt family of genes Named after the Drosophila gene wingless and one of its vertebrate homologs.

TGF-β family Includes:  TGF-β itself  Bone morphogenetic protein (BMP) family  Activin family  Vg1 family .

kidney epithelial cells -differential development of the apical and basal sites – for reabsorption of solutes -renal tubular cell – primary cillium – to sense fluid flow and signal the cell to stop proliferating and to polarize .g. Cell Shape and Organization Cells need to organize themselves with respect to their position and polarity in the environment E.Polycystic kidney disease – loss function of polycystin 1 and 2 – failure to sense fluid flow – continue to proliferate – cysts .

developed from neural tube Neural stem cells forming the ventricular cell layer - divide to generate new neural stem cells as well as neuronal precursors – migrate outwards . Cell Migration Central nervous system .

Cell Migration Miller-Dieker syndrome -Lissencephaly (“ smooth brain”) -deletion in the LIS1 gene -loss of LIS1 gene function – progressive waves of migration of cortical neurons does not take place – thickened. hypercellular cerebral cortex with poorly developed gyri .

Cell Migration Waardenburg syndrome -abnormalities in neural crest development -hearing loss -defects in skin and hair pigmentation. coloration of the iris -mutation in 4 different transcription factors .

Programmed cell death Is necessary for the morphological development of many structures Apoptosis is required for the remodeling of tissues that form parts of the ventricular septum and cardiac outflow (endocardial cushions) – normal positioning of the origins of the aortic and pulmonary vessels When tissues remodel during morphogenesis. perforation of the anal membrane. during the separation of individual digits. communication between the uterus and vagina Defects of apoptosis – human congenital heart diseases (DiGeorge syndrome) .