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CMMB 403 > Midterm2 > Flashcards

Midterm2 Flashcards

1
Q

What progenitor cells can form from hemopoietic stem cell differentiation?

A

Myeloid progenitors
Lymphoid progenitors
The lineage a HSC takes is determined by the microenvironment it is in (signals)
- There are more than 100 billion blood cells replaced every day

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2
Q

Oct4

A

Marker for pluripotency

- Expressed in (early) inner cell mass cells, primordial/embryonic germ cells

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3
Q

Induced pluripotent stem cells (IPSC)

A

Differentiated adult cells can be reprogrammed to pluripotency WITHOUT an oocyte!
Gurdon - did it with an ooycyte
Yamanaka - did it without an oocyte

This can be done w/o an oocyte by using four defined transcription factors

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4
Q

What are the four defined factors required return a differentiated cell into a pluripotent one?

A

INDUCED PLURIPOTENT STEM CELLS
- Oct4 - c-Myc - Sox2 - Klf4

These are all transcription factors

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5
Q

Which are the types of cells which are most often replaced in the human body?

A

Blood and intestinal cells

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6
Q

Stem cell niche

A

A microenvironment within a tissue/organ that maintains adult stem cells in an undifferentiated state.

  • Where stem cell divides and proliferates
  • Environment where a stem cell can remain undifferentiated and self-renewing
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7
Q

Adult Intestinal Stem Cell Niche

A

In the crypt of the small intestine.

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8
Q

What are the ligand gradients present in the crypt of the small intestine?

A

Wnt2B - High at bottom, lower towards intestinal lumen

BMP4 - Low at the bottom, highest towards the intestinal lumen.

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9
Q

Role of Wnt2B in the intestinal stem cell niche?

A

Wnt2B is produced by stromal-mesenchymal cells at the base of the crypt. Wnt2B binds to receptors on CBCC.
Wnt2B signaling in CBCC stimulates cell proliferation and maintaining their stemness
Canonical signalling - Frizzled is receptor

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10
Q

Role of Bmp4 in the crypt of the small intestine?

A

Bmp gradient is highest near the intestinal lumen and lowest at base of crypt

  • Stimulates differentiation of intestinal cells
  • Released from stromal cells higher up, in the middle of the crypt region.
  • BMPs - TGF-β superfamily ligand (involves Smad 1,5 TF and Ser-Thr kinase activity)
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11
Q

What are the differentiated cell types of the small intestine?

A

Enterocytes: absorptive cells
Enteroendocrine cells: produce hormones necessary for intestinal function
Goblet cells: secrete mucus
Paneth cells: produce antimicrobial molecules + maintain the intestinal stem cell niche

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12
Q

What is anoikis?

A

Apoptosis when epithelial cells detach from a sheet. This happens after intestinal cells have lived out their 3-4 day life span and detach from the top of the villus

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13
Q

Paneth cells

A

These cells are in between the crypt base columnar cells (CBCC - the stem cells)

  • They produce antimicrobial compounds and Wnt3 (helps maintain stem cells as stem cells)
  • express a ligand, Dll4, for Notch signaling with CBCC.
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14
Q

CBCC

A

Crypt base columnar cell

  • Stem cell at the base of the crypt. Has Paneth cells in between
  • Expresses receptor for Wnt2b (a ligand produced by stromal, mesenchymal cells)
  • Further up in the crypt, the CBCCs express BMP4 receptors - BMP4 stimulates stem cell differentiation.
  • express Notch receptor for the ligand Dll4 expressed on Paneth cell membranes
  • Lgr5 is a marker for these stem cells
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15
Q

How is Notch signaling involved in the maintaining CBCCs as stem cells?

A

CBCC - express Notch receptor on cell membrane
Paneth cells express Dll4 (Notch ligand) on their cell membrane
This juxtacrine signalling maintains cell proliferation and their stemness.

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16
Q

Lgr5 involvement in intestinal stem cell niche

A

Lgr5 is expressed only in CBCCs
It is a receptor that responds to R-spondin ligand in Canonical Wnt Pathway
Wnt signalling is required to maintain CBCCs as stem cells
-R-spondin binding to Lgr5 receptors prevents the degredation of the Wnt complex

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17
Q

What signaling pathway do R-spondin ligands trigger?

A

Canonical Wnt Signalling

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18
Q

What are the stem cell niches within the bone marrow?

A

Endosteal Niche

Perivascular Niche

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19
Q

Endosteal Niche

A

Stem cell niche of hematopoietic stem cells of the bone marrow

  • HSCs here are long term, typically in a quiescent state
  • HSCs are adhered to osteoblasts which release chemokine called CXCL12. HSCs have a receptor for these chemokine.
  • The HSCs in this niche can replace the ones in the shorter term niche
  • Cadherins are also involved
  • Jagged-Notch signaling and VCAM + cadherin are critical.
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20
Q

What transmembrane receptors do HSCs express?

A

CXCR4 - a GPCR that binds to CXCL12 that has been released by osteoblasts and CARs cells.

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21
Q

Perivascular niche

A

HSCs in this niche are associated with the blood vessels within the bonemarrow.
-The HSCs in this niche are relatively short term and actively dividing
-

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22
Q

How does noradrenaline play a role in the Circadian rhythm aspect of blood cell division?

A

Sympathetic neurons have axons connecting to the bonemarrow and release NE. This communicates to cells within the bonemarrow to stop producing CXCL12, a chemokine.
- Thus NE SLOWS DOWN the proliferation and division of blood cells.
NE inhibits expression of CXCL12 in CARs cells and others.

NE binds to receptors on CARs cells and other mesenchymal/stromal cells - inhibits expression of CXCL12

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23
Q

Is NE released moreso during the day or night? What is the result of this differential release?

A

NE (noradrenaline) is produced more in the day to slow down proliferation of blood cells.
Blood cells enter the blood stream

NE (norepinephrine) is not produced as much at night, allowing more proliferation of blood cells. LESS SYMPATHETIC ACTIVATION

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24
Q

CXCL12

A
  • A chemokine that attracts HSC’s and primordial germ cells
    Released from osteoblasts in the endosteal niche of HSC. Recruits HSCs
  • Released from CARs cells in the perivascular niche
  • Binds to CXCR4 GPCR on HSC’s
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25
Q

CARs Cells

A

Perivascular niche of HSC
Wrap around blood vessels and release CXCL12
The CXCL12 binds to CXCR4 GPCRs on HSC membranes and allows them to maintain their stemness.
(CXCL12-abundant reticular cells)

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26
Q

XY Sex-Reversed Females

A

Could result from the deletion or a mutation of SRY on the Y chromosome, or mutation/deletion of Sox9 (haploinsufficient)
These individuals are sterile because

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27
Q

XX Sex Reversed Males

A

These individuals are sterile because there are other genes present on the Y chromosome necessary for sperm development.
translocation of SRY to another chromosome. Mutation of Rspo1

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28
Q

What cells act as the germ cell niche in the developing gonads?

A

The supporting cells! either the sertoli or granulosa cells

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29
Q

What causes Sertoli cells to form?

A

Somatic cells differentiate into sertoli cells due to Sox9 being activated by Sry TF binding to enhancer 13.
- leads to testis development

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30
Q

What causes granulosa cells to form?

A

The somatic cells in the developing gonad become granulosa cells due to express of Rspo1 and Wnt4
- leads to ovary development

31
Q

Which tissues form from the intermediate mesoderm?

A

the gonads and the kidneys

  • mesonephros (transient)
  • metanephric tissue (where the mature kidney is formed form)
32
Q

Mesonephros

A

Tissue in the developing embryo that is derived from the intermediate mesoderm

  • Transient kidney structure in the embryo. The transient collecting duct for this tissue becomes the Wolffian duct.
  • The gonadal tissue is derived from intermediate mesodermal tissue adjacent to the mesonephros
33
Q

What tissues does the Mullerian duct eventually develop into?

A

fallopian tubes, uterus, and most cranial part of the vagina, cervix

The hormones secreted by the cells in the gonad are what cause the differentiation and development of the external genitalia

34
Q

genital ridge

A

ventral thickening of the epithelium and underlying mesenchyme of the mesonephros that is a precursor of the gonads

35
Q

What causes the Mullerian duct to degenerate?

A

Normally this occurs in males.
Production of anti-mullerian hormone/factor by the Sertoli cells
degrades the Mullerian duct
- Recall that Sox9 expression results in bipotential support cells becoming Sertoli cells.

36
Q

What causes the Wolffian duct to degenerate?

A

This normally occurs in females. High levels of testosterone are needed to maintain the Wolffian duct.
Thus, the wolffian duct will degenerate if there is not enough testosterone present - OR if cells cannot respond to the testosterone.

37
Q

What tissues form from the Wolffian duct?

A
  • Vas deferens, epididymis, seminal vesicle

The hormones secreted by the cells in the gonad are what cause the differentiation and development of the external genitalia

38
Q

At what week in human development do the gonads begin to differentiate along one of the two pathways?

A

8 weeks!

At 6 weeks, the primordial germ cells (bipotential) arrive at the genital ridge and both mullerian and wolffian ducts are present.

39
Q

Sertoli cells

A

Produce AMF in males. AMF then goes on to degenerate the mullerian duct.
- This is an ACTIVE process

Pre-Sertoli cells- express Sry

40
Q

AMH

A

Antimullerian hormone/factor - produced by the Sertoli cells

  • Degrades the mullerian duct
  • a TGF - β superfamily ligand –> subfamily Nodal-related –> thus it has phosphorylation of Smad2,3
41
Q

leydig cells

A

Derived from the intermediate mesoderm

produce testosterone in testes

42
Q

Klinefelter syndrome

A

Individual has XXY. This idvl is how humans determined that what determines male sex is the presence of a Y chromosome rather than 2 X’s

  • bc idvls with this syndrome have a male phenotype
  • Also absence of Y would give females
43
Q

Turner sydrome

A

Idvls only have one X chromosome
Display female phenotype – bc they do not have an X
- If 2 X’s were required for an individual to be female, then this idvl would not be female.. but she is
-further proof that it is the absence of a Y that determines one to be female.

44
Q

What is the testis determining factor?

A

Sry! Presence of the SRY gene on the short arm of the Y chromosome that causes testis formation. Sry is expressed in the pre-sertoli cells of the developing gonad

-Sry begins to be expressed at ~6 weeks in development

45
Q

Sry

A

Gene expressed in pre-sertoli cells in males.
Gene codes for a TF, a HMG domain containing TF (DNA binding domain)
- Codes for testis determining factor
- Expression of this gene only occurs for a short time -but Sox9 is activated for a long time after.
- Related to Sox9 - SRY was the first SOX gene to be discovered

Sry protein binds to Enhancer 13 to activate Sox9 expression
Appeared ~200 million years ago `

46
Q

Sox9

A

Gene activated in response to SRY protein binding enhancer 13
Expression of this in genital ridge–> get a male
Expression of these gene in all vertebrates will result in a male forming under normal conditions
- Expression of Sox9 causes sertoli cells to develop.
- Knockout Sox9 gene in XY idvls - get sex reversal to female

47
Q

How to get female?

A
  • Absence of SRY and activation of the canonical WNT pathway
  • Wnt signalling stabilizes B-catenin which allows the right genes to be expressed in granulosa cells
  • BOTH Rsp1o and Wnt4 are required to stabilize B-catenin - get ovary development
  • theca cells produce estrogen
48
Q

Sox9 & B -catenin interaction

A

reciprocal inhibition of eachother
reinforces set-out pathway
- mutually inhibitory interactions promote one pathway over another.

49
Q

What may happen if B-catenin is not stabilized enough in the gonad?

A

Sex determination may swing over to testis development because Wnt4, Rspo1 and the downstream results of this (including B -catenin stabilization) is necessary for ovaries to form
- testes may develop in this case, even in the absence of Sry and Sox9 activation!

50
Q

What happens if Rspo1 is dysfunctional in females?

A

‘Pendulum’ of sex determination swings over to testes/males

Loss of Rspo1 was the first loss of function mutation discovered that causes complete female to male sex reversal

51
Q

Rspo1 protein role in sex determination

A

Rspo1 is a secreted ligand protein that amplifies Wnt signals and stabilizes β catenin.

  • NECESSARY for female sex determination (without it, you become male)
  • Rspo1 expression is specific to the somatic cells of the female gonads.
52
Q

What happens in Androgen insensitivity syndrome?

A
  • XY idvls with female secondary sex characteristics (look female, some have testes)
  • These individuals can make testosterone, but they are unable to respond to it as they don’t have a functional androgen or testosterone receptor – thus they can’t express genes that testosterone generally signals for.
  • Both the mullerian duct and the wolffian duct degenerate
53
Q

Where is retinoic acid synthesized and what does it do?

A

In the mesonephros of BOTH males and females. Retinoic acid stimulates meiosis to start.

  • This happens during embryonic development (when eggs begin to form in females). The males, an enzyme called Cyp26B1 expressed and released that causes the degredation of RA.
  • Meiosis of male germ cells doesn’t occur until puberty.
54
Q

What does Cyp26B1 do?

A

It is an enzyme produced in the male gonads. It degrades retinoic acid to prevent meiosis from occurring.
- This enzyme is expressed up until puberty.

55
Q

Where do primordial germ cells form?

A

They form in the posterior portion of the epiblast and gastrulate through the posterior primitive streak where they associate with the
endoderm that will form the gut.

They are set aside away from lots of the signaling molecules present in the environment during gastrulation

56
Q

What attracts primordial germ cells to the genital ridge?

A

CXCL12 (Sdf1) chemokine secreted by the genital ridge.
PGCs express the receptor, CXCR4 (a GPCR) on their cell membrane, which the CXCL12 binds to
- cells around the PGCs also produce Steel (stem-cell factor) ligand which binds to the membrane receptor c-Kit (RTK)

57
Q

What does the Steel ligand bind to and what does this do?

A

It is a ligand released from cells surrounding the primordial germ cells. It binds to a receptor tyrosine kinase called c-Kit on the membrane of primordial germ cells
This, in combination with CXCL12 signaling from cells of the genital ridge, results in the migration of the PGCs from the hind gut to the genital ridge.

58
Q

leptotene

A

Stage before synapsis but following DNA replication

59
Q

zygotene

A

See synapsis beginning and synaptonemal complex proteins are present

60
Q

pachytene

A

homologous chromosomes are completely synapsed - recombination occurs here

SYCP1 - lots expressed here because of complete synapsis.

61
Q

diplotene

A

Synapsis begins to end, desynapsing occurring.

62
Q

What stage in meiosis do cells become haploid?

A

After anaphase 1 (meiosis 1)

The first meiosis is thus called the reductional division.

63
Q

What is a marker for meiosis?

A

Synaptonemal complex protein expression! SYCP1

64
Q

At which state is meiosis paused at during oogenesis in the developing female embryo?

A

At week 12 in development, the meiosis of female germ cells pauses in diplotene stage (first meiotic prophase). Doesn’t continue again until a few eggs begin maturing every month @ puberty.

65
Q

What is retinoic acid?

A

It is a signaling molecule (not a protein) that is synthesized in the mesonephros.
It is a derivative of vitamin A that activates transcription of Stra8 transcription factor (necessary for meiotic initiation)
It is mostly hydrophobic and thus functions through nuclear receptors
It stimulates the beginning of meiosis, unless Cyp26B1 is there to degrade it (in males)

66
Q

What does Nanos2 do in terms of meiosis stimulation?

A

It is an RNA binding protein expressed in males that prevents Stra8 mRNA from being translated to protein. This prevents Stra8 from acting as a TF and promoting meiosis initiation.

67
Q

What kind of cleavage does a zebrafish have? Mero or holoblastic

A

meroblastic cleavage

68
Q

Holoblastic cleavage

A

Entire egg is cleaved into cells.

Xenopus frogs undergo this type of cleavage

69
Q

meroblastic cleavage

A

The entire egg is not cleaved into cells. Happens when there is a lot of yolk (yolk inhibits cleavage to some extent)

70
Q

centrolecithal cleavage

A

A form of meroblastic cleavage -

Only the rim of the egg is cleaved and that is because the yolk is in the centre and yolk isnt cleaved.

71
Q

What happens during gastrulation?

A

The three germ layers are formed and the nervous system is induced
- Very important part of human development

72
Q

What does Slug protein do?

A

Repress the expression of the E-cadherin gene. It turns on a TF that represses the E-cadherin gene

73
Q

Which transcription factors need to be present for delta crystallin gene to be transcribed?

A

L-Maf - produced when FGF8 ligand binds surface ectoderm cellls
Sox-2 - produced when BMP4 binds surface ectoderm cells
Pax-6

74
Q

What pathway is Ras in and what does it do?

A

Ras is present in the RTK pathways (FGF ligands). Ras is a monomeric G protein bound to GDP generally when no ligand is present. When a ligand is present, GEF will mediate the exchange of GDP for GTP on Ras. Ras GTP can then activate Raf, a protein kinase C

CMMB 403 (7 decks)

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