Disturbances in Growth and Differentiation

Embryology

Teratology

Oncology

Embryology

Coordinated events

Physiologic Stimuli

Hormones

Growth factors

Nutrients

Blood Supply

Tissue/Cell interactions (cell-cell communication)

Cell Differentiation and Regeneration

The capacity for tissue repair following injury depends on the ability of the terminally differentiated cells to replicate and the presence of tissue stem cells

Renal Dysplasia vs. Chronic Renal Failure

Teratology

TeratologyStudy of Developmental Anomalies

2% of live births have major abnormality

Up to 5% if minor abnormalities included

Cultural differences

Etiologies of Birth Defects

Cyclopia

Veratrum californicum14th day of gestation

protruding lower jaw, underdeveloped upper jaw, proboscis-like nose, cyclopia, hydrocephaly, other ocular defectsprolonged gestation

hypothalmic-pituitary-adrenal axis

17-19 days of gestationtracheal stenosis

28-31 days of gestationshortened metatarsal and metacarpal bones

Errors of MorphogenesisDevelopmental Syndrome

Developmental Syndrome

Aborted minature foal

Hydrocephalus

Brachygnathia superior

Metacarpal-digital and metatarsal-digital varus

Errors of MorphogenesisDeformation

Arthrogryposis

Cache Valley Virus

oligoamnios

Lupinosis

CNS malformation

Errors of MorphogenesisDeformation

Spina Bifida

Spina Bifida

Cleft Palate

Relationship Between Genotype and Phenotype

Epigenetic Events • Histone de-acetylation• DNA methylation• Micro RNA

• Downregulation

Interplay Between Environment and Genotype

CarcinogensChemical

Radiation

OncovirusesPapilloma

Lymphoma

Sarcomas

Inflammation

DNA repair defects

Tumor suppressor gene defects

Mutations

Genome mutations (gain/loss of whole chromosomes)

Chromosome mutations (altered structure)

Single gene mutations

Cytogenetics

Types of Chromosome Mutations

Spectral Karyotyping

Molecular Diagnostics

FISH- Interphase nucleus- Green probes for Chr 13, and Red for Chr 21 (trisomy 21)

FISH- Multicolor FISH- Shows portion of chromosome 22q to chromosome 9

Microarray- Gene Chip (left) – used to sequence thousands of base pairs of DNA. Close up view of hybridization pattern of the microarray.

Single Gene Mutations

Target genesEnzymesReceptorsStructural proteinsCell growth regulators

Different mutations may have vastly different effects

Mechanisms of Single Gene Mutations

Amino Acid Substitution

Premature Termination

Frameshifts

Diagnosis of Single Gene Mutations

“Molecular Pathology”

Errors of MorphogenesisSensitivity to Teratogenic Agents

Errors of MorphogenesisAgenesis vs. Aplasia

Errors of MorphogenesisHypoplasia vs. Abiotrophy

Errors of MorphogenesisDysraphism

Spinal bifida and menigomyelocoele

Errors of MorphogenesisEctopia

Errors of MorphogenesisDystopia

Errors of MorphogenesisDysplasia

Neoplasia

Disturbances of Cell Proliferation

Epithelium Reversible

Reversible

Reversible

Cell CycleG1/S Checkpoint- Cyclin D/CDK4, Rb, P53

G2/M Checkpoint- Cyclin A/CDK2

Cell Cycle-Stages

G0- Resting Cells

G1-preparation for division(G for growth)

S- DNA synthesis

G2- Preparation for cell division

M- Actual mitosis

Cell types• Non-Dividing

– Permanent G0

• Neurons, Cardiac muscle, Skeletal muscle

• Quiescent (Stable tissues)

– G0-G1 transition when stimulated

• Liver, kidney, pancreas, mesenchymal tissues, vascular

• Continuously Dividing (Labile)

– Never in G0

• Epithelia, Bladder, glands

• Arise from tissue stem cells

Cell Cycle- Regulation• Proto-Oncogenes

– Growth Factors, Transcription factors stimulated by growth factors or involved in signaling by growth factors

– Necessary for progression through cell cycle checkpoints• Cyclins, CDK’s, c-fos, c-jun- c-

myc, PDGF, RAS

• Tumor Suppressor Genes– Monitor DNA damage and

lead to arrest of cell cycle or apoptosis• P53, Rb

• DNA repair genes

• Apoptosis genes

Cell Cycle

Cancer Genetics

THE END!