Chapter 16-- Development, Stem Cells, and Cancer Overview--Orchestrating Life's Processes ● Sequence of genes being turned on and off = regulation of gene expression ● Model organisms ○ Species that are easy to raise in the lab and experiment on ■ Fruit fly ● Fertilized egg --- larva --- adult wing --- adult ● Stem cells = hope for medical treatments ● Proper gene expression is crucial to functions of life 16.1) A Program of Differential Gene Expression Leads to the Different Cell Types in a Multicellular Organism ● Embryonic development ○ Fertilized egg gives rise to many different types ■ Each with different structure and function ● cells -- tissues-- organs --- organ systems--- organisms A Genetic Program for Embryonic Development ● zygote -- organism is a remarkable transformation ○ Three interrelated processes ■ Cell division ■ Cell differentiation ■ Morphogenesis ● Mitotic cell division = large number of cells ● Cell division ○ Produce great ball of identical cell ● Differentiation ○ During embryonic development ○ Cells become specialized in structure and function ● Morphogenesis Chapter 16-- Development, Stem Cells, and Cancer Overview--Orchestrating Life's Processes ○ Organism shape ○ Traced back to changes in motility, shape, etc. of cells ● Activities of cell depend on the gene expression and protein production ○ Form fits function ● Almost all cells in organism have the same genome ● Materials placed into the egg by the mom = program of gene regulation ○ Carried out as cells divide ○ Causes cells to become different from each other Cytoplasmic Determinants and Inductive Signals ● Specific genes expressed in developing organism determine its path ● Two sources of information ○ One source = egg cytoplasm ■ Contains both RNA, proteins, and organelles ● Distributed unevenly in unfertilized egg ■ Cytoplasmic determinants ● Combination helps determine its developmental fate ○ Second source = environment around the cell ■ Contact with cell - surface molecules on neighbor cells ■ Such contact changes the target cells ● Induction Sequential Regulation of Gene Expression During Cellular Differentiation ● Cell development = cell structure and function become noticeably different ● Determination ○ Unseen events that lead to observable differentiation of a cell ○ Once undergone an embryonic cell committed to its final fate Differentiation of Cell Types Chapter 16-- Development, Stem Cells, and Cancer Overview--Orchestrating Life's Processes ● Outcome of determination is marked by expression of genes ○ Tissue specific proteins ● Tissue specific proteins ○ Found only in a specific cell type ○ Give cell characteristic and function ● First sign of differentiation = appearance of mRNAs for these proteins ● Differentiated cells = specialists at making TSP ○ Liver cells making albumin ■ These cells are long fibers containing many nuclei ● Within a single plasma membrane ○ Skeletal muscle cells = higher conc. Of MSP ● Muscle cells develop from embryonic precursor cells ○ Have potential to develop into a number of cell types ■ Cartilage and fat ● Particular conditions commit them to become muscle cells ● MyoD = mast regulatory gene ● Regulation of genes -- important to development of tissues and structure Apoptosis: A Type of Programmed Cell Division ● Apoptosis ○ Programmed cell death ○ Occurs in cells of mature organism ■ Infected ■ Damaged ■ Reached the end of functional life span ○ Cellular agents chop DNA ■ Fragment organelles and cytoplasmic components ○ Cell become multilobed ○ Cell´s parts are packaged into vesicles ○ Protects neighbor cells from damage that they would suffer ■ If a dying cell leaked out its contents ● Digestive enzymes ○ Plays crucial role in embryo development Chapter 16-- Development, Stem Cells, and Cancer Overview--Orchestrating Life's Processes ○ Essential to development and maintenance of all animals ○ In vertebrates ■ Essential for normal development of nervous system ■ Normal morphogenesis of hands and feet in humans and paws ● Tissues to function properly = organism's body plan Pattern Formation: Setting Up the Body Plan ● Pattern formation ○ Spatial organization which tissues and organs are all in their place ○ Begins in the early embryo ■ When major axes of an animal are established ● Positional information ○ Molecular cues that control pattern formation ○ Provided by cytoplasmic determinants and inductive signals ○ These cues tell a cell its location ■ Relative to the body axes and to neighbor cells ○ Determine how the cell and pogany will respond to future molecular signals ● Genes can control development The Life Cycle of Drosophila ● Fruit flies -- modular structure ○ Ordered series of segments ■ Three major parts ● Head ● Thorax ● Abdomen Genetic Analysis of Early Development: Scientific Inquiry Chapter 16-- Development, Stem Cells, and Cancer Overview--Orchestrating Life's Processes ● Homeotic genes ○ Control pattern formation in the late embryo, larva, and adult ● Number of Drosophila protein coding genes = 13,900 ● Mutations affect process as fundamental segmentation ○ Embryonic lethals ■ Mutations with phenotypes causing death ● At embryonic or larval stage ■ Cannot be bred for study ● Cytoplasmic determinants in the egg ○ Known to play a role in axis formation ● 1200 genes essential for pattern formation during embryonic development ○ 120 essential for normal segmentation Axis Formation ● Maternal effect gene ○ When mutant in the mother ■ Results in mutant phenotype in the offspring ● Regardless of the offspring's own genotype ● Egg polarity genes ○ Control the orientation of the egg Bicoid: A Morphogen Determining Head Structures ● Bicoid ○ Two tailed ○ Embryo whose mother has two mutant alleles of bicoid gene ■ Lacks the front half of its body ■ Posterior structure that both ends ● Morphogens ○ Establish embryo´s axes and other features of its form ● Maternal mRNAs are crucial during development of many species ● Change in gene regulation during during develop can lead to change in body Chapter 16-- Development, Stem Cells, and Cancer Overview--Orchestrating Life's Processes 16.2) Cloning of Organism´s Showed That Differentiated Cells Could Be ¨Reprogrammed and Ultimately Led to the Production of Stem Cells ● Genes are not lost ● Stem cells = generate many different tissues Cloning Plants and Animals ● Single cells taken from the root and incubated in culture medium ○ Able to grow into a normal adult plants ■ Genetically identical to parent plant ● In plants cells can dedifferentiate ○ Give rise to to all specialized cell types of the organism ■ Totipotent ● Differentiated cells from animals generally do not divide in culture ● Nuclear transplantation ○ Remove nucleus of an unfertilized or fertilized egg ○ Replace it with the nucleus of a differentiated cell ● Potential of transplanted nucleus to direct normal development ○ Inversely related to the age of the donor ■ Older the donor, older the nucleus ■ Lower % of normally developing tadpoles ● Something in nucleus does change as animal cells differentiate Reproductive Cloning of Mammals ● Reproductive cloning ○ Cultured mammary cells in nutrient poor medium ○ Fused these cells with enucleated sheep eggs ○ Resulting diploid cells divided to form early embryos ● Environmental and random phenomena can play role during develop Faulty Gene Regulation in Cloned Animals ● Regulation often is result of epigenetic changes in chromatin Chapter 16-- Development, Stem Cells, and Cancer Overview--Orchestrating Life's Processes ○ Acetylation of histones ○ Methylation of DNA ● During nuclear transfer procedure ○ Many of these changes must be reversed in later stages ● Reprogramming of donor nuclei ○ Require more accurate and complete chromatin restructuring ● DNA of donor nuclei may interfere with pattern of gene expression Stem Cells of Animals ● Stem cell ○ Relatively unspecialized cell ○ Can reproduce its indefinitely ○ Differentiate into specialized cells of one or more types ○ Replenish their own undifferentiated population ○ Generate cells that travel down specific differentiation pathways ● Many early animal embryos contain stem cells ○ Capable of giving rise to differentiated embryonic cells of any type ● Stem cells can be isolated from early embryos at a stage called blastula stage ● Embryonic stem cells ○ Reproduce indefinitely ○ Can be made to differentiate into a wide variety of specialized cells ■ Egg and sperm ● Adult stem cells ○ Serve to replace non reproducing specialized cells as needed ○ Not able to give rise to all cell types in the organism ■ Can generate many type ● Blood cells ● Bone , cartilage, fat, muscle, lining of blood vessels ● Adult brain ● Ultimate aim is to supply cells for repair of damaged or diseased organs ● Pluripotent Chapter 16-- Development, Stem Cells, and Cancer Overview--Orchestrating Life's Processes ○ Capable of differentiating into many different cell types ● ES cells obtained from embryos donated by patient undergoing infertility treatment ○ Or from long term cell cultures ■ Established with cells isolated from donated embryos ● Therapeutic cloning ○ ES cells to treat disease ● Induced pluripotent stem ○ Could do everything ES cells can do ○ Difference in cell division ● Two major potential uses for human iPS cells ○ Cells from patients suffering a disease can be reprogrammed into iPS ■ Can act as model cells for studying the disease ● Potential treatments ○ Patient's own cell can be reprogrammed into iPS cells ■ Used to replace nonfunctional tissues 16.3) Abnormal Regulation of Genes That Affect the Cell Cycle Can Lead to Cancer ● Gene regulation systems go wrong during cancer ○ Very same systems that play a role in embryonic development ■ Also maintenance of stem cell populations ■ Many other biological processes Types of Genes Associated with Cancer ● Genes that normally regulate cell growth and division ○ Include genes for growth factors, receptors, and intracellular molecules ● Mutations that alter any of these genes in somatic cells can lead to cancer ● Likely many cancer causing mutations come from environmental influences ○ Chemical carcinogens ○ X-Rays ○ High energy radiation Chapter 16-- Development, Stem Cells, and Cancer Overview--Orchestrating Life's Processes ○ Some viruses ● Oncogenes ○ Cancer causing genes in some viruses ○ Close counterparts found in genomes of humans ■ Viral oncogenes ○ Proto - oncogenes ■ Normal versions of the cellular genes ■ Code for proteins that stimulate normal growth and division ○ Arises from a genetic change ■ Leads to increase in proto-oncogenes protein product ○ Genetic change fall into three main categories ■ Movement of DNA within the genome ■ Amplification in a control element ■ In the proto-oncogene itself ● Cancer cells frequent to find chromosomes that have broke and joined incorrect ● Movement of DNA ○ Translocated proto-oncogene ends up near promoter ■ Transcription may increase ● Making it an oncogene ● Amplification ○ Increases number of copies of proto-oncogene in cell ■ Repeated gene duplication ● Point mutation ○ In the promoter of an enhancer that controls a proto-oncogene ■ Causing an increase in the expression ○ In the coding sequence of the proto-oncogene ■ Changing the gene´s product to protein ● More active or more resistant to degradation ● All of these mechanisms can lead to abnormal stim of the cell cycle ○ Putting it on the path to become malignant ● Tumor suppressor genes ○ Encode proteins that help prevent uncontrolled cell growth ○ Any mutation that decreases the normal activity ■ May contribute to the onset of cancer Chapter 16-- Development, Stem Cells, and Cancer Overview--Orchestrating Life's Processes ● Stimulating growth through the absence of suppression ○ Various function ■ Repair damaged DNA ● Prevents the cell from accumulating cancer causing mutations ■ Control the adhesion of cells to each other or to EM ■ Components of cell signaling pathways ● Inhibit the cell cycle ● Ras gene ○ Connective tissue cancer ○ G protein that relays a signal from GFR --- protein kinases ○ Mutations lead to production of hyperactive ras protein ■ Triggers the kinases ● Increased cell division ● P53 gene ○ 53,000-dalton molecular weight of its protein product ■ Tumor suppressor gene ● Activator for several other genes ○ Often activates another gene -- p21 ■ Product halts the cell cycle ● Binding to cyclin kinases ○ Activate expression of a group of miRNAs ■ Inhibit the cell cycle ○ Can turn on genes directly involved in DNA repair ○ Activates ¨suicide¨ genes ■ Protein products bring about apoptosis The Multistep Model of Cancer Development ● More than one somatic mutation is generally needed ○ Production of all the changes of a full cancer cell ● Colorectal cancer develops gradually ○ First sign is usually a polyp ■ Small benign growth in the colon lining ○ Tumor grows and may eventually become malignant ○ Develop of tumor is paralleled by gradual accumulation of mutations ■ Convert proto-oncogenes to oncogenes ● Knockout tumor suppressor genes Chapter 16-- Development, Stem Cells, and Cancer Overview--Orchestrating Life's Processes ● 6 changes must occur at DNA level for a cell to become fully cancerous ○ Appearance of at least one active oncogene ○ Mutation or loss of several TSG Inherited Predisposition and Other Factors Contributing to Cancer ● Multiple genetic changes required to produce a cancer cell ● 15% of colorectal cancer is inherited ● APC ○ Multiple functions in the cell ■ Regulation of cell migration ■ Adhesion ○ Mutated in 60% of colorectal cancers ● 5-10% with breast cancer -- inherited ○ Second most common type ○ BRCA1 ■ 50% of inherited breast cancers ● Risk of cancer can be lowered by minimizing exposure to DNA damaging agents ○ Ultraviolet radiation in sunlight and cigarette smoke ● Tumor viruses ○ Can cause cancer in various animals and humans ● Viruses can interfere with gene regulation ○ Viral integration may donate an oncogene to the cell ■ Disrupt a TSG ■ Convert a proto-oncogene to an oncogene ● Tumor suppressor genes can make the cell more prone to becoming cancerous
