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Developmental Biology Ch 16. Development of an organism (especially a human) has fascinated people since the beginning of recorded history. How does a.

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Presentation on theme: "Developmental Biology Ch 16. Development of an organism (especially a human) has fascinated people since the beginning of recorded history. How does a."— Presentation transcript:

1 Developmental Biology Ch 16

2 Development of an organism (especially a human) has fascinated people since the beginning of recorded history. How does a full-fledged organism “appear” from little more than mixing fluids during sex? Where is the identity of the adult found? Leonardo, , developing fetus Nicholas Hartsoeker, 1694, visualizing what sperm must contain, tiny people! Anton Leeuwenhoek is credited with “discovering” sperm in the late 1600s, a little over 300 years ago. His report to the Royal Society stated “What I investigate is only what, without sinfully defiling myself, remains as a residue after conjugal coitus.”

3 Development is the phenotypic change over the lifetime of an organism, from Brooklyn hipster to frog to roses to oak trees. Change is continuous although we often identify artificial “stages” by time (day, year, decade) or by structures (seed, flower, prepubescent, gray hair)

4 Animal development is very similar in all animals

5 Development poses one of the biggest challenges in understanding regulation of genetic expression. How does expression of genes change from fertilization through the many continuous stages of development? We elaborate from what we know about regulation of gene expression from the lac operon through epigenetics and then add in the complicating factor of time. For the “environment” of a gene, we now add the cell’s cytoplasm as well as neighboring cells to the influence of distant cells, the outside environment (both living and non-living.)

6 Animal cloning reveals that the nucleus of a differentiated cell has ALL the information to regulate cell growth and differentiation. Once placed in the right ENVIRONMENT (cell cytoplasm), genomic information can be EXPRESSED to result in a new organism. This approach is in the early stages of research and does not always work!!

7 QUESTION: how does a single cell (zygote) divide into many varieties of cells (differentiate) that also organize into specific shapes and functions (morphogenesis)? QUESTION: How does cell variety come about when all daughter cells of the zygote have the same genotype? Animal development, whether in starfish or butterflies or worms or humans, has a great deal in common: formation of a hollow ball of cells (blastula), followed by invagination of growing cells to form a gastrula that will develop into the gut region.

8 In normal development, cell fates typically become determined As embryos form a blastula and gastrula, cells begin to take on “mature” (differentiated) characteristics, and cells in different regions of an embryo are “fated” to develop into specific cell types. The breadth or narrowness of a cell’s fate generates different names. TOTIPOTENT cells are not fated and can develop into a new organism. Stem cells are MULTIPOTENT and can form several but not all cell types. PLURIPOTENT can form all cell types but not an entire organism.

9 Stem cell is a term that’s mistakenly often used to mean progenitor cells. Stem cells replace themselves during their first mitotic division. Progenitor cells don’t replace themselves but may differentiate into more than one kind of cell. Also called a precursor cell One daughter cell is like the parent stem cell Both daughter cells are specialized

10 APC is the adenomatous polyposis coli gene on chromosome 22. Loss of APC leads to benign adenomatous polyps, frequently seen during colonoscopy. DCC is deleted in colorectal cancer gene, a ligand-dependent suppressor gene. p53 is a tumor suppressor gene involved with many cell-cycle activities, including activating normal cell death, called APOPTOSIS. Mutated p53 genes are associated with a majority of cancers (though not all). p53 is also involved with normal cell-cycle arrest. Human Papilloma Virus (HPV) strains 16 & 18 are oncogenic. Two viral proteins inactivate p53 and pRB, cell cycle check-point proteins.

11 Another look at colon cancer development. Notice that several mutations need to occur before cancer occurs. APC mutations occur frequently and early — many people have polyps. Other mutations are necessary for cell adhesion to break down.. K-RAS (KRAS) is a G-protein signaling molecule sensitive to growth factors. Mutated KRAS leads to cell overgrowth. Finally, mutations in p53 decrease apoptosis. Mutations in MLH1 and MSH2 decrease DNA repair Mutations in p53 appear to slow apoptosis and allow tumor angiogenesis, leading to adenocarcinomas.

12 Cancer is viewed as an abnormality of development. When stem cells divide, one daughter cell becomes a progenitor (ancestor) of normal cells that will differentiate, function and usually die. The other daughter cell replaces the parent stem cell, so the number of stem cells remains essentially constant, though some stem cells die out. If gene expression is altered so that either a progenitor or stem cell no longer matures and differentiates correctly, it may continue to divide as an unregulated, immature cell that mimics characteristics of the embryo without functioning as a mature, differentiated cell — a malignancy (cancer) has been formed. Cancer GRADE refers to the degree of differentiation Cancer STAGE refers to the spread of a tumor

13 Contractile muscle cells are found in all animal groups, from round worms to insects to fish to mammals. Development of muscle cells from non-muscle progenitor cells has been heavily studied. Specific transcription factors act with epigenetic mechanisms to control muscle development and postnatal muscle remodeling, for example into slow-twitch or fast-twitch muscle fibers. All this involves SIGNALING CASCADES controlled by extracellular growth factors, cytokines, steroid hormones and mechanical activity. At the core of muscle DIFFERENTIATION from general precursor cells is a muscle-specific transcription factor MYOD. Disruption of the MYOD gene completely abolishes muscle cell formation. The transcriptional cascade depends on molecules released by neighboring cells in the embryonic neural tube. ON

14 Muscle Development During development, mesodermal stem cells divide to several types of progenitor cells (blood, bone, liver, muscle). MYOD transcription factor binds to p21 promoter, stops cell cycle and launches mesodermal stem cells to differentiate into muscle stem cells called myoblasts. Myoblasts differentiate further by “downstream” expression of more than 50 muscle-specific genes. MYOD-associated deacetylase keeps myoblasts undifferentiated through epigenetic means until extracellular signals from neighboring neural tube activate differentiation. Then factor P/CAF allows acetylation of histone, opening of DNA and transcription of myogenin for further differentiation of myoblasts to muscle cells. Typically muscle stem cells die out and humans are left with the same number of muscle cells they have at age 2. The cells do not divide but do get significantly larger and also can undergo mitosis without cytokinesis. New nuclei appear but the cells don’t divide to daughter cells.

15 Cutting the early mass of cells (early blastula) into two sides results in two normal embryos and two normal larval stages and two adults. Cutting the cells into top half and bottom half results in nearly normal embryo from bottom but no further development by top-half cells. Restoring a group of bottom-half cells called micromeres allows top half to develop to larva (almost normal). The micromeres must contain key molecules, CYTOPLASMIC DETERMINANTS, that influence the development of top-half cells by inducing changes in more distant cells. INDUCTION of development changes in one cell can come from distant cells in the environment. Restoration of cytoplasmic determinants released by micromeres restores normal larval development.

16 An important inducer molecule is RETINOIC ACID (RA), derived from conversion of vitamin A (retinol) to retinal and then to retinoic acid. Since retinoic acid induces changes in cell organization related to an organ’s shape, it’s often called a MORPHOGEN. In absence of RA, a transcription heterodimer, RXR-RAR is bound to DNA and co-repressors. As with early mesodermal cells that repress muscle development, the RXR-RAR complex causes histone deacetylation and nucleosome winding into heterochromatin, regulation of the epigenome. Binding of RA induces conformation changes, the binding of co-activators and histone acetylation that is associated with activation of transcription. Too much or too little RA during development is associated with birth defects. Excess leads to overdevelopment of posterior regions of a tissue while RA deficiency leads to overdevelopment of anterior regions.

17 More on retinoic acid A different view of previous slide. Retinol (vit A) is converted to retinal which is converted to retinoic acid (RA). Ultimately, RA is oxidized and excreted. Without RA, a co-repressor binds to a heterodimer to the RARE promoter, leading to histone deacetylation and no transcription With RA, histones are acetylated, and transcription proceeds. What environmental influence on epigenetic regulation by RA might occur??

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