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Bio 127 - Section III Organogenesis Part 1

Bio 127 - Section III Organogenesis Part 1. The Stem Cell Concept The Emergence of the Ectoderm Neural Crest Cells and Axonal Specificity Paraxial and Intermediate Mesoderm. I. Stem Cells Role in the Development of Tissues and Organs. Gastrulation produces the three germ layers

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Bio 127 - Section III Organogenesis Part 1

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  1. Bio 127 - Section IIIOrganogenesis Part 1 The Stem Cell Concept The Emergence of the Ectoderm Neural Crest Cells and Axonal Specificity Paraxial and Intermediate Mesoderm

  2. I. Stem Cells Role in the Development of Tissues and Organs • Gastrulation produces the three germ layers • Germ layer interactions induce organogenesis • More and more we see that this requires the development of stem cells and their ‘niches’ • Places that these cells can remain relatively undifferentiated and yet provide differentiated progeny

  3. A. The Stem Cell Concept • Division of stem cells produces one new stem cell and one differentiated daughter • Sometimes potential is unrealized and you get two new stem cells • In some organs: frequent replenishing divisions • gut, epidermis, bone marrow • example: billions of blood cells are destroyed by the spleen every hour • In others, they only divide in response to stress or the need to repair the organ • heart, prostate

  4. b. Stem Cell Terminology HSC Totipotent = zygote and 4-8 blastomeres Pluripotent = inner cell mass, “ESC” COMMITTED STEM CELLS: Multipotent = adult stem cells hematopoietic, mammary, gut Unipotent = adult stem cells spermatogonia, melanocyte

  5. Maturational series of neuronal stem cells VOCABULARY

  6. c. Types: Embryonic Stem Cells

  7. c. Types: Adult Stem Cells • Committed stem cells with limited potential • hematopietic stem cells - hair stem cells • mesenchymal stem cells - melanocyte stem cells • epidermal stem cells - muscle stem cells • neural stem cells - tooth stem cells • gut stem cells - germline stem cells • mammary stem cells • Hard to extract and culture • HSC are less than 1 in 15,000 bone marrow cells • Transplants work very well, however • Mammary, neural, muscle, others all being worked on

  8. c. Types: Mesenchymal Stem Cells • Surprising degree of differentiation plasticity • muscle, fat, bone, cartilage • PDGF, TGF-B, FGF combinations determine fate • Found in lots of niches in both embryo and adult • umbilical cord blood, baby teeth • marrow, fat muscle, thymus, dental pulp • Paramedic response to injury • Migrate from niche to provide paracrine stimulus to repair injured tissues w/wo differentiating on-site

  9. 2. The Stem Cell Niche • Part of organogenesis in many tissues requires developing special sites for stem cells to live • Microenvironments wherein the cells that stay don’t differentiate but those that leave do • Unique combinations of local paracrine signaling, cell-ECM and cell-cell interactions

  10. Hematopoietic stem cells and the bone marrow niche -Both are Committed Stem Cells -Progenitor cells can’t self-renew This is what allows us to do bone marrow transplants

  11. So, what’s going on in the bone marrow niche? Controls on differentiation: -bone cell matrix -stromal paracrine factors -pericyte paracrine factors -systemic hormones -neuronal signals Hematopoietic stem cells can form all blood cells. Mesenchymal stem cells can migrate to injury sites. So far..... Wnt angiopoietin stem cell factor Delta-Notch Integrin-ECM

  12. The mouse tooth stem cell niche (we don’t have one) A balance of “positive – negative” FGF3 – BMP4 and activin -- follistatin

  13. Stem cell niche in Drosophila testes The ‘hub’ consists of ~12 somatic cells: the cells in direct contact with them remain stem cells, while the daughters without contact become sperm progenitors Hub cells  Unpaired  JAK-STAT  Stem Cell Division

  14. Stem cell niche in Drosophila testes Cadherins appear to hold first centrosome close to the ‘hub’

  15. Niche Break-Down May be Part of Aging • Too much cell differentiation • Can deplete the capacity for renewal • Graying hair may result from too many melanocyte differentiations • Too much cell division • Cancers may result from excess division • Myeoloproliferative disease is too much marrow division without differentiation

  16. Neurulation is a developmental process that takes the organism from the gastrula stage through development of a functional central nervous system Structure  Process  Structure

  17. The first organ system to begin development in vertebrates is the central nervous system Two Major Steps: 1. Formation of the neural tube 2. Differentiation of neurons

  18. REMEMBER: Hensen’s Node (chick) and Spemann’s Organizer (frog) pass organizing power to the notochord Secreted factors from the notochord cause neurulation in ectoderm above

  19. Interestingly, the primary mechanism is by means of inhibition....

  20. Figure 9.1 Major derivatives of the ectoderm germ layer Differentiated Phenotypes Ectodermal Competencies

  21. So, where are we starting?

  22. Establishing Neural Cells from the Ectoderm • Competence: multipotent cells with the ability to form neurons with the right signals • Specification: the right signals are there but cell change could still be repressed by other signals • Determination: the cells have entered the neuronal pathway and cannot be repressed • Differentiation: the cells leave the mitotic cycle and express the genes characteristic of neurons

  23. As the node regresses, it leaves the notochord behind anterior to posterior and the overlying neural plate starts to form neural tube in the same pattern Primary Neurulation Secondary Neurulation

  24. Combining Primary and Secondary Neurulation to form the Neural Tube • Primary = Folding of the Neural Plate into a tube structure directly • Secondary = Mesenchymal Coalescence followed by hollowing out into a tube • The Neural Tube proper results from the joining of the two

  25. In Birds: everything anterior to the hind limbs is Primary Neurulation • In Mammals: the sacral vertebrae back through the tail is Secondary Neurulation • In Amphibians and Fish: only the tail is Secondary Neurulation

  26. Primary Neurulation in the Chick As much as half of the ectoderm can be induced to form neural plate! neural convergent extension combined with epidermal epiboly Neural plate cells elongate into columnar epithelium medial hinge point cells are anchored to notochord MHP cells flatten and become wedge-shaped to facilitate bending

  27. Primary Neurulation in the Chick dorsolateral hinge points form between neural and epidermal cells, not crest as the tube nears closure, neural crest cells undergo EMT and migrate away Birds close at mid-brain and “zip” in 2 directions Mammals have three primary points of closure *remember: closure results from neural cells switching from E- to N-cadherin

  28. Works the same on the dorsal surface of amphibian “sphere”

  29. Human Neural Closure Neural tube defects are common: 1 in 1000 live births -spina bifida: posterior neuropore -anencephaly: anterior neuropore -craniorachischisis: the whole tube

  30. Folate Supplementation Reduces Rate of Defects Folate-binding protein in the neural folds as neural tube closure occurs A fungal contamination of corn produces the teratogen fumonisin that appears to disrupt the function of FBP

  31. Secondary Neurulation The coalescence of the two neural tubes is not well understood and may be important in some defects

  32. Differentiation of the Neural Tube • Three simultaneous levels of development • Gross anatomy: bulges and constrictions form the chambers of the brain and spinal cord • Tissue anatomy: the cell populations in the wall rearrange to form functional domains • Cell biology: the neuroepithelial cells differentiate into neurons and glia • Two simultaneous axes of development • Anterior-Posterior: the forebrain back toward the spinal column • Dorsal-Ventral: the axis from the roof plate of the tube, near the epidermis, and the floor plate, near the notochord

  33. Figure 9.9 Early human brain development (Part 1)

  34. Figure 9.9 Early human brain development (Part 2)

  35. Rhombomeres of the chick hindbrain Neural crest cells from above specific rhombomeres form the cranial nerve ganglia r1 r2 5th trigeminal r3 r4 7th facial and 8th vestibuloacoustic r5 r6 9th glossopharyngeal r7

  36. The size of the vertebrate brain increases very rapidly in early neurulation due to an osmotic Na+ gradient dumped into the presumptive ventricle: for example, the chick’s brain volume increases 30-fold from day 3-5 The increase in size determines how many neurons are able to ultimately divide and form

  37. Occlusion of the neural tube allows expansion of the future brain Relaxes after expansion

  38. Anterior-Posterior Specification of Neurons: Evolutionary conservation of homeotic gene organization and transcriptional expression in fruit flies and mice

  39. Dorsal-ventral specification of the spinal neural tube

  40. Dorsal-ventral specification of the spinal neural tube Sensory Input Motor Output

  41. Concentration Gradient-Dependent Transcription Factor Expression growth factors transcription factors TGF-B Pax7 Pax6 Shh Nkx6.1

  42. Differentiation of Neurons in the Brain • Neuroepithelium of neural tube starts as one layer of stem cells • Humans have 100 billion neurons and 1 trillion glial cells • Neuroepithelium gives rise to: • Ependymal cells: line the ventricles, secrete CSF • Neurons: electrical, regulation, thought, senses • Glia: brain construction, neuron support, insulation and maybe memory storage?

  43. Diagram of a neuron We have very few dendrites at birth, up to 100,000 connections in 1st year! microtubules follows signal gradient can be 2-3 feet long

  44. Figure 9.16 Axon growth cones Actin microspikes provide migratory traction and signal sensing

  45. Figure 9.17 Myelination in the central and peripheral nervous systems Multiple sclerosis is a demyelination disease

  46. Neural stem cells in the germinal epithelium Neural tube start as one layer of stem cells, all in the cell cycle Stem cell divisions are all horizontal Position of nucleus depends on cell cycle

  47. Neuron Birthdays • Differentiating cells are born from vertical divisions • Stem cell stays attached, distal sister migrates away and leaves the cell cycle • Early birthdays form closer layers, later birthdays form more distal layers • Neuronal function, neurotransmitter type and connections formed depends on Anterior-Posterior, Dorsal-Ventral position (eg. Hox, TGF-B v. Shh )

  48. Complexity Increases the Further Anterior You Go Initially three basic layers are formed stem cells cell bodies “gray matter” myelin axons “white matter”

  49. Figure 9.20 Development of the human spinal cord Original formation of the germinal neuroepithelial layer Differentiated three adult layers: 1. ventricular zone = ependyma 2. Intermediate zone = mantle 3. Marginal zone = myelin layer Becomes encased in connective tissue

  50. Figure 9.19 Differentiation of the walls of the neural tube (Part 1)

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