lecture 12 disturbances in growth and differentiation
TRANSCRIPT
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!