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Neuroscience: Exam 3 > Lecture 9: Neurogenesis > Flashcards

Lecture 9: Neurogenesis Flashcards

1
Q

List the necessary conditions to be considered a Stem Cell

A
  1. Proliferation
  2. Self-renewal
  3. Production of differentiated functional progency
  4. Regenerating the tissue after injury

As for now, studies show little overlap in the genes identified as defining “stemness”→There are no unique markers to identify NSC

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2
Q

What are the lineage of a stem cell?

A
  • Totipotent Stem Cell
  • Committed Stem Cell
  • Comitted Progenitor
  • Differntiated Cells

Review Slide 4

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3
Q

What is an Embryonic Stem Cell (ESC) and it’s origins?

A
  • Found in the inner cell mass of the blastocyst (fertilized egg)
  • From there it can begin differentiation to produce 3 germ layers and their respective stem cells, committed progenitors, and ultimately differentiated cells
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4
Q

What are the 3 germ layers produced by the ESC?

ESC-Embryonic Stem Cell

A
  1. Endoderm
  2. Ectoderm
  3. Mesoderm
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5
Q

What is the committed stem cell(s) derived from the ectoderm?

A

Neural Stem Cell (NSC)→CNS

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6
Q

What are the comitted progenitors produced by the NSC?

NSC-Neural Stem Cell

A
  • Neuronal Precursors (Neuroblast)
  • Glial Prescursors (Glioblast)
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7
Q

What are the differentiated cell produces by neuroblast and glioblast?

A
  • Neuroblast→Neuron
  • Glioblast→Oligodendrocytes
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8
Q

How is the development of Microglia different from the other neuronal cells?

HIGH

A

They exist in the CNS, BUT they develop from mesoderm, not ectoderm

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9
Q

List the 3 main processes Neurogenesis is dependent on

A
  1. Proliferation
  2. Differentiation
  3. Migration

NOTE: these processes are not necessarily sequential

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10
Q

List the steps at the beginning of Neurogenesis involving the Cell Cycle

Cell Birth

A
  1. In G1, the nucleus is near the ventricular surface
  2. During the S stage, the nucleus and surrounding cytoplasm migrate toward the pial surface, and DNA replicates
  3. During G2, cells grow and the nucleus migrates toward the lumen again
  4. In mitosis, cells lose their connection to the pial surface and divide.
  • The symmetrical division generates two neural stem cells. Asymmetrical divisions generate a neuroblast and a progenitor cell with limited mitotic potential

Review Slide 8

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11
Q

What is Interkentic Nuclear Migration?

A
  • Migration of the nucleus (toward and away from pial surface) throughout the cell cycle
  • Guided by Radial glia

This process involves molecular proteins Dyenin and Kinesin

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12
Q

What is Cell Proliferatiion?

A

The process of multiplying the number of cells

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13
Q

What is Cell Differentiation?

A

The process of forming different cell types which form tissues and organs that have specific functions within the body

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14
Q

What determines whether a stem cell goes through proliferation or differentiation?

A

Type of Division

  • Symmetric (Vertical) Division
  • Asymmetric (Horizontal) Division
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15
Q

What is the fate of a cell that goes through Symmetric(Vertical) Division?

A
  • Proliferation
  • Same fate: expansion of cell population (i.e. neural stem cells)
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16
Q

What is the fate of a cell that goes through the Asymmetric(Horizontal) Division?

A
  • Differentiation and Proliferation
  • Different fate: Expansion of stem cell population while also producing differentiated cells (i.e. neurons)
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17
Q

List the important Growth/Tropic Factors that influence prolieration (3)

HIGH yield

A
  • FGF-2(bFGF)
  • EGF
  • Neurotrophins (BDNF/NT3/NT4)
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18
Q

List other factors that influence proliferation (4)

A
  • Ephrins & Eph receptors
  • Adhesion Molecules
  • Polycomb group (PcG) proteins
  • Hedgehog
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19
Q

Explain the function of growth/trophic factor: FGF-2(bFGF)

Proliferation

A
  • In early embryonic NSCs & predisposes toward a neuronal fate
  • Induces slow proliferation
  • Lack bFGF receptors during development leads to reduce reduced neurons and glia in cortex while administerinf bFGF leads to increased neurons in cortex
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20
Q

Explain the function of growth/trophic factor: EGF

Proliferation

A
  • Expressed later in development around the time of gliogenesis
  • Vigorous proliferation
  • Deletion of receptors lead to defect in cortical neurogenesis
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21
Q

Explain the function of growth/trophic factor: Neurotrophins (BDNF/NT3/NT4)

Proliferation

A
  • Act through tropomysin (trk) receptors B&C
  • Enhance NSC survival
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22
Q

Explain the function of factor: Ephrins & Eph receptors

Proliferation

A
  • Ephrin B2 and EphB2 ↑ proliferation
  • Ephrin A2 ↓ differentiation
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23
Q

Explain the function of factor: Adhesion Molecules

Proliferation

A

NCAM and CD24 ↑ proliferation & modify migration

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24
Q

Explain the function of factor: Polycomb group (PcG) proteins

Proliferation

A
  • Form multiple polycomb repressive complexes (PRCs) which bind to DNA & modify chromatin structure, silencing genes
  • Essential for earliest stages of vertebrate development
  • Components of PRC2 that are required for activity: EZH2, SUZ12, EED
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25
Q

Explain the function of factor: Hedgehog

Proliferation

A

Hedgehog ↑ leads to ↑ in proliferation

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26
Q

What is the role of microRNA in development?

A

Small noncoding RNA that regulate gene expression by base pairing to mRNAs

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27
Q

What are the two ways to determine the cell fate during Differentiation?

A
  • Intrinsic
  • Extrinsic
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28
Q

Explain the Intrinsic mechanism of Differentitation

A
  • Molecules expressed in progenitor
  • Forwared to progeny through invariant patterns of mitosis

Molecule that triggers differentiation is IN the cell

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29
Q

Explain the Extrinsic mechanism of Differentitation

A
  • Receptor-mediated
  • Autocrine, paracrine or endocrine
  • Modify transcription

Factor that triggers differentiation is OUTside of the cell

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30
Q

List the Differentiation Extrinsic Factors (4)

A
  • BMP/TMP-β
  • PDGF/EGF
  • Cytokines (Il-6/CNTF/LIF)
  • EGF-like receptors/Notch

Other factors:
Extracellular Matrix
Adhesion Molecules/Integrins

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31
Q

Explain the function of the extrinsic factor: BNP/TGF-β

Differentiation

A
  • Can induce neurons or astrocytes

Regulated primarily via the concentrations of each of the BMPs and their antagonist

32
Q

Explain the function of the extrinsic factor: PDGF/EGF

Differentiation

A
  • Earliest marker of an oligodendrocyte precursors
  • Once fate is committed, both PDGF-a & b are present
  • Once fate is committed, EGF promotes further differentiation
33
Q

Explain the function of the extrinsic factor: Cytokines(IL-6/CNTF/LIF)

Differentiation

A
  • Important for astrocytes and oligodnedrocytes fate

There is a gp130 subunit & a cytokine specific sununit

34
Q

Explain the function of the extrinsic factor: EGF-like receptor/Notch

Differentiation

A
  • Required for glial fate specification
35
Q

List the Differentiation Intrinsic Factors ( 3)

A
  • bHLH
  • Co-associating Proteins
  • Coactivators and Corepressors
36
Q

Explain the function of intrinsic factor: bHLH

Differentiation

A
  • Mash-1, Neurogenin 1&2→neurons
  • Olig 1&2→Oligodendrocytes
37
Q

Explain the function of intrinsic factor: Co-associating Proteins

Differentiation

A
  • Hes-1, Prox-1, Inhibitor of Differentiation (ID)
  • Antagonize Mash-1 (which help create neurons)
38
Q

Explain the function of intrinsic factor: Coactivators and Corepressors

Differentiation

A
  • CREB binding protein (CBP)/p300→astrocytes
  • Acts at the STAT binding element within the GAP promoter
39
Q

What is the first differentiated cells in the ventricular zone (VZ) during neural development?

Migration

A

Radial glia (scaffolding cells)

40
Q

Where is the location and function of the Radial glia?

Migration

A
  • Location: Radial foot processes extend from ventricular zone to pial zone
  • Function: Acts a primary guidance pathway for postmiotic neurons
41
Q

List the factors the are expressed that play a role in the Migration Process (5)

A
  • Reelin
  • Vimentin
  • Nestin
  • S-100B
  • GLAST

All factors EXCEPT Reelin play a “structural role” as it relates to migration

42
Q

What is the function of the migration factor: Reelin

A

Push migrating neurons off radial glial

43
Q

Radial migration occurs _________ as the cortical layers are established.

A

First

44
Q

What different patterns of migrations are observed in later stages of development?

A
  • Tangential Migration
  • Anterior-Posterior Migration
45
Q

Explain Tangential Migration and what factors play a role.

A
  • Formation of cortical interneurons
  • Factors: Nkx2.1,Dlx1,Dlx2, Mash2
46
Q

Explain Anterior Posterior Migration and what factors play a role,

A
  • Newborn neurons from the subventricular zone travel to the olfactory bulb through the rostral migratory stream
  • Factors: PSA-NCAM, Reelin, Ephrins, Tenascin-R
47
Q

List the primary differences between Fetal Neurogenesis and Adult Neurogenesis (3)

A
  1. It must occur in a permissive environment (needs protection from anti-neurogenic influences)
  2. Individualized (smaller scale) process NOT a population event
  3. Quiescene Hypothesis
48
Q

What are the permissive environment(s) that adult neurogenesis can occur?

A
  • Subventricular Zone (SVZ)
  • Subgranular Zone (SGZ)

Regions are well vascularized and can be influenced by local and circulating regions

49
Q

What processes occur at the SVZ and SGZ?

Adult Neurogenesis

SVZ=Subventricular Zone
SGZ=Subgranular Zone

A
  • SVZ→Mainly neurons
  • SGZ→Some neurons and some glia
50
Q

Explain Quiescence Hypothesis

Adult Neurogenesis

A
  • NSC’s slowly proliferate and produce transit amplifying cells which are main proliferating cells

Parellels the hematopoietic system in which some stem cells would be noncycling quiescent stem cells locked in G0 while others are actively engaged in the cell

51
Q

If deplete all proliferating cells in SVZ, _________ can repopulate

A

GFAP+ astrocytes

52
Q

What is the order of receptor formation in Embryo Neurogenesis?

HIGH yield

A
  1. Voltage dependent Na+→Action Potential
  2. GABAa-R→Depolarization
  3. NMDA-R→Depolarization
  4. AMPA-R→Depolarization
53
Q

What is the order of receptor formation in Adult Neurogenesis?

A
  1. GABAa-R→Depolarization (?)
  2. AMPA-R→Depolarization
  3. NMDA-R→Depolarization
  4. Voltage dependent Na+→Action Potential
54
Q

What is the major difference between the receptor formation of embryo and adult neurogensis? Why?

A
  • Developing adult neurons DELAY the formation of voltage-gated Na+ channels UNTIL they are fully integrated into the neural circuitry.
  • This is to prevent unwanted AP firing during migration.

As the cells radially migrate in the olfactory bulb (OB) they recieve synaptic inputs but they remain unable to fire they are fully integrated into the neural circuitry

55
Q

What is the function of Adult Neurogensis in the Subventricular Zone (SVZ)?

A

New neurons in the SVZ replace older neurons with the olfactory bulb

Review 25, 26 & 28

56
Q

List the steps of adult neurogenesis in the SVZ.

A
  1. Migration via the RMS (rostral migratory stream) is mediated by PSA-NCAM and other chemoattractive/repulsive signals (integrins, ephrins, astrocytes)
  2. Once the cells reach OB, reelin mediates detachment from the tangential chain, and Tenascin directs cells to the final destination in granule cell layer.
  3. New cells become interneurons NOT projection neurons
  4. Granule neurons have no axons, and their output is mediated by bidirectional dendrodendritic synapses with mitral and tufted cells
  5. Process takes 15-30 days

Anterior-Posterior Migration

1% of the NSC becomes preglomerular cells

57
Q

What is the function of Adult Neurogensis in the Subgranular Zone (SBZ)?

Hippocampal Neurogenesis

A

Cellular proliferation occurs in sub-granular layer of the dentate gyrus

Review 27 & 28

58
Q

List the steps of adult neurogensis in the SGZ?

A
  1. Cells migrate into the granular cell layer where they extend dendrites then axons through the hilus and into Ammons horn/ CA3 (No long distance-migration)
  2. Neurogenesis is interspersed with gliogenesis
  3. Process occurs over 4-7 weeks
  4. Responsive to FGF-2
  5. Most newly generated cells will die

  • Do NOT form neurospheres in culture
  • Do NOT undergo long-distance migration
  • About 15% form glial cells
59
Q

Why does neurogensis decrease with Age?

A
  • Fewer Stem Cells
    1. ↑ cell cycle time
    2. Terminal differentiation
    3. Cell death
  • Environmental Changes
    1. ↓ trophic support
    2. ↓ migration
    3. Altered local cues
  • Age Related Changes
    1. ↓ cellular metabolism
    2. Oxidative damage
    3. DNA & protein damage
    4. ↓ mitochondrial function
    5. Altered telomerase biology
    6. Altered gene expression

Review 29 & 30

60
Q

What are the 2 ways stem cells play a role in brain repair?

A
  1. Endogenous Neural Stem Cells
  2. Cell Therapy
  • Neural Replacement
  • Environmental Support
  1. Neurotransmitter
  2. Trophic Support
  • Choice of Cells
61
Q

Is there adult neurogenesis after injury (i.e. stroke)?

Endogenous Stem Cells

A
  • Yes
  • Study 1: Neurogenesis increases in SVZ and SGZ after MCAO
  • Study 2: Neurogensis increases in SVZ in people after ischemic stroke

Review Slides 35 and 36 for Studies

MCAO (Middle Cerebral Artery Occlusion) Model of Stroke

62
Q

Do the newborn cells integrate into existing neurocircuitry after an injury?

Endogenous Stem Cells

A
  • Yes
  • Study 1: It is believed that astrocytes/microglia release factors which draw newborn cells to sites of injury.
  • Study 2: Newborn cells release the appropriate neurotransmitters.
  • Study 3: Newborn cells are electrically active

Review Slide 37,38, & 39 for Studies

63
Q

Are Endogenous Stem Cells Reparative?

A
  • NOT so much
  • Study 1: Newborn cells don’t necessarily target the appropriate neurons and could lead to epilepsy due to unwanted AP firing.

Review Slide 40

64
Q

Can Endogenous Neurogensis be enhanced by adding growth/trophic factors?

A
  • Study 2: We do some increases in neural stem cell proliferation but it’s not enough
  • Some factors have shown effective: Erythropoietin (EPO), Neutrophins, IGF-1, VEGF

Review 41

65
Q

Can stem cell transplants repair a damaged brain?

Stem Cell Therapy

A
  • Seems like yes!
  • Study 1: Showed improved behavioral outcome, increased differentiated cells surrounding the lesion, and decreased size of the lesion.

Review Slide 44

66
Q

List the advantages of Stem Cell Transplantation

A
  • Can expand the cell population
  • Can differentiate into many different cell types
  • The cell migrate
  • The cells have the potential to integrate into mature brain circuity
  • Low immunogenicity
67
Q

What is the mechanism of recovery? (4 studies)

Stem Cell Therapy

A
  • There are several
  • Study 1:Replacement of Missing Factor Production of appropriate neurotransmitters at appropriate locations.
  • Study 2:Trophic Effects Neurotrophic factors (i.e. NT-3) lead to increases in neuronal fibers.
  • Study 3: Decreased Inflammation-2hr IV infusion post injury of Neural Stem Cells (NSC) led to significant decreases in inflammation.
  • Study 4: Target Delivery System-NSC migrate to the site of tumors. In other words, they can be used as a targeted delivery system to fight injury/disease

Review Slides 44-46

68
Q

List the many stem cell niches throughout the body

A
  • Embroyonic Stem Cell
  • Fetal
    1. Neural stem cell is one type
  • Adult
    1. Bone marroe derived (hematopoietic, mescenchymal & endothelial progenitor)
    2. Neural stem cell
    3. Adipose derivved
    4. Umblicial cord (blood and tissue)
    5. Induced Pluripotent Stem Cells (iPSCs)
69
Q

What are Induced Pluripotent Stem Cells (iPSCs)?

A

Induced pluripotent stem cells are a type of pluripotent stem cell that can be generated directly from a somatic cell. These cells can develop into MANY different types of cells or tissues in the body (one size fits all).

70
Q

How are Induced Pluripotent Stem Cells formed?

A
  • Patient fibroblasts are reprogrammed with master regulators of pluripotency: c-Myc, OCT4, Klf-4, and SOX2.
  • iPSC colonies are then formed which can be used to form neural precursor cells via dual-SMAD inhibition.
71
Q

What is the Best Cell Type to Transplant?

A
  • Umbilical Cord Blood Cells
  • 48 hours post-stroke→80% decrease in damage due to an interruption of inflammatory responses.

Info from Study: Slide 52

  • Behavioral Test Include: Step test, EBST, Rotorod, Activity
  • Cell Doses: 10^6 i.v.
  • Timing of Transplant: 3,24,48,72,168 hr or 30 days post MCAO
72
Q
  1. Scientists at the Morsani College of Medicine are studying the differentiation of glioblasts using extrinsic factors. To do so, they significantly increase production of PDGF in study mice and analyze cellular quantities post-mortem. Given the study procedure, which of the following glial cells will likely have the greatest concentrations?
    A. Astrocytes
    B. Oligodendrocytes
    C. Both
    D. Neither
A

B. Oligodendrocytes

73
Q
  1. All of the following growth/tropic factors contribute to the proliferation of neural stem cells EXCEPT:
    A. FGF-2
    B. Neurotrophins
    C. Ephrin B2
    D. Notch
A

D. Notch

74
Q
  1. During neural development, radial glia are the first differentiated cells in the ventricular zone and act as a primary guidance pathway for developing neurons. How would the absence of Reelin affect the function of these cells?
    A. Cellular proliferation would be less pronounced
    B. Their structural role would be impaired
    C. Migrating neurons would be unable to detach
    D. Their foot processes would be unable to reach the pial surface
A

C. Migrating neurons would be unable to detach

75
Q
  1. Which of the following structures are interconnected by the rostral migratory stream?
    A. Subventricular zone & Olfactory bulb
    B. Dentate gyrus & Ammons horn
    C. Subventricular zone & Ammons horn
    D. Dentate gyrus & Olfactory bulb
A

A. Subventricular zone & Olfactory bulb

76
Q
  1. Stem cell therapy, also known as regenerative medicine, promotes the repair response of diseased or injured tissue using stem cells. According to Dr. Willing, which of the following cell types would be most effective at decreasing damage associated with inflammation following MCAO?
    A. Induce pluripotent stem cells
    B. Umbilical cord blood cells
    C. Fetal neural stem cells
    D. Embryonic stem cells
A

B. Umbilical cord blood cells

Neuroscience: Exam 3 (9 decks)

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