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Disturbances in Growth and Differentiation
Embryology
Teratology
Oncology
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Embryology
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Coordinated events
Physiologic Stimuli
Hormones
Growth factors
Nutrients
Blood Supply
Tissue/Cell interactions (cell-cell communication)
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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
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Renal Dysplasia vs. Chronic Renal Failure
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Teratology
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TeratologyStudy of Developmental Anomalies
2% of live births have major abnormality
Up to 5% if minor abnormalities included
Cultural differences
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Etiologies of Birth Defects
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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
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Errors of MorphogenesisDevelopmental Syndrome
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Developmental Syndrome
Aborted minature foal
Hydrocephalus
Brachygnathia superior
Metacarpal-digital and metatarsal-digital varus
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Errors of MorphogenesisDeformation
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Arthrogryposis
Cache Valley Virus
oligoamnios
Lupinosis
CNS malformation
Errors of MorphogenesisDeformation
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Spina Bifida
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Spina Bifida
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Cleft Palate
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Relationship Between Genotype and Phenotype
Epigenetic Events • Histone de-acetylation• DNA methylation• Micro RNA
• Downregulation
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Interplay Between Environment and Genotype
CarcinogensChemical
Radiation
OncovirusesPapilloma
Lymphoma
Sarcomas
Inflammation
DNA repair defects
Tumor suppressor gene defects
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Mutations
Genome mutations (gain/loss of whole chromosomes)
Chromosome mutations (altered structure)
Single gene mutations
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Cytogenetics
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Types of Chromosome Mutations
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Spectral Karyotyping
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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
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Microarray- Gene Chip (left) – used to sequence thousands of base pairs of DNA. Close up view of hybridization pattern of the microarray.
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Single Gene Mutations
Target genesEnzymesReceptorsStructural proteinsCell growth regulators
Different mutations may have vastly different effects
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Mechanisms of Single Gene Mutations
Amino Acid Substitution
Premature Termination
Frameshifts
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Diagnosis of Single Gene Mutations
“Molecular Pathology”
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Errors of MorphogenesisSensitivity to Teratogenic Agents
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Errors of MorphogenesisAgenesis vs. Aplasia
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Errors of MorphogenesisHypoplasia vs. Abiotrophy
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Errors of MorphogenesisDysraphism
Spinal bifida and menigomyelocoele
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Errors of MorphogenesisEctopia
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Errors of MorphogenesisDystopia
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Errors of MorphogenesisDysplasia
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Neoplasia
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Disturbances of Cell Proliferation
Epithelium Reversible
Reversible
Reversible
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Cell CycleG1/S Checkpoint- Cyclin D/CDK4, Rb, P53
G2/M Checkpoint- Cyclin A/CDK2
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Cell Cycle-Stages
G0- Resting Cells
G1-preparation for division(G for growth)
S- DNA synthesis
G2- Preparation for cell division
M- Actual mitosis
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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
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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
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Cell Cycle
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Cancer Genetics
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THE END!