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D&D > Somitogenesis > Flashcards

Somitogenesis Flashcards

1
Q

Where does the somite originate from?

A

Paraxial mesoderm (which forms into sclerotome, myotome and dermatome)- produced by the presomitic mesoderm

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2
Q

What doe the intermediate and lateral mesoderm differentiate into?

A

Intermediate mesoderm- kidney and gonads

lateral mesoderm- splanchnic, somitic, extra-embryonic

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3
Q

What is the presomitic mesoderm (PSM) generated by?

A

The cranial (rostral) primitive streak & the tail bud, involving proliferation, specification and emigration

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4
Q

What pathways are invovled in somitogenesis and how do they interact?

A

Wnt, FGF, RA and BMP pathways are required, interacting with each other directly or indirectly, via positive & negative feedback loops

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5
Q

How does the embryo grow during somitogenesis?

A

Traditionally, the PSM is thought of as “regressing” that is moving backwards, leaving somites behind as it goes. In fact, the whole embryo is growing during this phase, and all tissues are moving, relative to one another

  • somites laid down sequentially, cranial to caudal
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6
Q

In what manner are somites formed (e.g. spacially, temprorally)?

A

Formed regularly, with the time characteristic of the species (e.g. 1 pair each in 2h mouse, ~5h human, 1.5h chick)

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7
Q

What does the number of somite pairs developed depend on?

A

The total somites formed also characteristic of the species, independent of variations in embryonic size (e.g. zebrafish 33 pairs, human 44, mouse 65)

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8
Q

How do somite halves differ?

A

Cranial & caudal somite halves are different

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9
Q

What encodes somite fate?

A

Each somite has different fate, encoded in the PSM by Hox genes

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10
Q

How are somites initially paired and what do thety differentiate to?

A 
Initially paired epithelial spheres each side of neural tube
Differentiate to:
Dermomyotome and sclerotome (vertebrae)
Myotome: epimere, hypomere, limb muscle
Dermatome: dorsal dermis
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11
Q

What is the fate of the most cranial 5 somites?

A

Occipital bone

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12
Q

What does the notochord develop into?

A

Nuclues pulposus

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13
Q

What happens if neural arches fail to fuse?

A

Spina bifida occulta

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14
Q

What abnormalities of the sclerotome exist?

A 
Abnormal segmentation
Hemivertebrae, or fused vertebrae
Scoliosis (lateral curve of spine)
Klippel-Feil syndrome (brevicollis)
Short neck, reduced number of cervical vertebrae
Failed fusion or non-union of arches 
Spina bifida occulta
Non-union of sternum: Split xiphoid process
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15
Q

What is the Fate of the myotome?

A

Myotome into epimere, hypomere, limb muscle

Epimere: epaxial extensor muscles of spine
Dorsal ramus of spinal nerve

Hypomere: flexors of spine; outer, intermediate, inner layers in thorax & abdomen
Ventral ramus of spinal nerve

Nerve/muscle segmentation

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16
Q

Where do nerves grow in from?

A

Nerves grow in from spinal nerves of neural tube

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17
Q

What are Myoblasts attracted by?

A

Myoblasts attracted by HGF (scatter factor, only in limb field mesoderm; c-met receptor in myotome)

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18
Q

What are muscle patterns dicated by?

A

Connective tissue

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19
Q

Why do muscles produce trophic signals?

A

For nerves to follow

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20
Q

What does dermatome form?

A

Dermis, subdermal connective tissue

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21
Q

What is the fate of the dermatome?

A

Dermatome: area of skin supplied by a single spinal nerve & its ganglion

Dorsal dermis from dermomyotome

Adjacent spinal nerve - sensory innervation

Initial segmental pattern in limb buds converted to proximo-distal pattern

Rotation of limbs: opposite fore & hind

Outwards fore: elbows caudal
Inward hind: knees cranial

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22
Q

How is differentiation of the somite controlled?

A

LOL JOKE HAHAHAHA

The slide says:

Shh secreted from notochord, along with NT-2, Wnt1,3 from the dorsal neural tube and BMP4/FGF from the lateral plate mesoderm = contributes to somite differentiation

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23
Q

What do the signalling molecules involved in somitogenesis differentiate?

A

Notochord secretes Shh which induces Pax1 in ventral paraxial mesoderm to produce sclerotome.

Wnt1/3 released from dorsal (roof) plate of neural tube induces Myf5 in medial part which forms body wall muscles

NT-3 also secreted from neural tube acts on dorsal part of mesoderm which will form dermis

Wnt secreted from epidermis and BMP4/FGF from lateral plate mesoderm induces Pax3 and MyoD in lateral paraxial mesoderm which will form epaxial muscles

(read slide 20 of somitogenesis it’s lit)

24
Q

What is the syndetome?

A

The syndetome is the progenitor population for tendons

25
Q

Name properties of the somite halves: cranio-caudal

A

Cranio-caudal halves of somites have different properties

Neural crest migration
Motor neurone migration
Formation of vertebrae

Specified in PSM, before somite boundary formation

Several genes expressed in half stripes in somitomeres S0 and S-1

Caudal half: HES1, Delta1 (Notch signalling)
Cranial half: MesP (bHLH, Mesp2 nulls lose cranial identity), EphA4 (EPH receptor)

26
Q

What do Cranial & caudal halves make?

A

Centrum

27
Q

Where do intersegmental arteries between somites come to lie?

A

Midway over bodies

28
Q

Why do myotomes bridge intervertebral disks?

A

So they can move vertebrae

29
Q

Where do spinal nerves pass through?

A

Spinal nerves pass through somites, but come to run through intervertebral foramina

30
Q

Where is somite axial identitiy encoded?

A

Presomitic mesoderm

31
Q

What TF is important in somitogenesis?

A

Hox genes-
Hox genes bind DNA in a sequence-specific fashion

They regulate expression of adjacent/nearby genes

Confer positional identity along the A-P (cranio-caudal) axis of the trunk
(highly conserved)

32
Q

Desribe Hox gene evolution

A

Vertebrates have 4 Hox gene clusters, which have arisen from two duplication events of an ancestral chromosome

Gene order along the chromosome corresponds to the position of expression within the embryo

Gene transcription within each Hox cluster displays spatio-temporal co-linearity

33
Q

Why are Hox genes important?

A
  • they are involved in somite identity

- code their vertebral region (e.g. cervical/thoracic/lumbar/sacral/caudal

34
Q

How is the regular formation of somites achieved?

A

The clock and wavefront model

In theory, what is needed is a clock mechanism to mark time, plus a wavefront or “trigger” to form a somite at each set period

Oscillations of the clock are generated by delayed negative feedback on gene expression

The trigger is provided by a gradient(s) threshold(s) of signalling proteins

35
Q

Have ago at explaining the wave of gene expression in somitogenesis

(good luck xxx)

A

PSM cells have cyclic gene expression, with the same period as somite production: part of the somitogenesis clock. Typically, there is an apparent wave in PSM, and a persistent stripe cranially (rostrally). The “wave” is actually rapid switching on and off of expression, and suggests close coupling between cells, which has been shown in real time at the single cell level using a luciferase reporte

36
Q

Describe the three-tier model of segmentation clock

A

bottom tier: single cell oscilators- so gene expression transcribes and translates protein which then inhibits further gene expression in a negative feedback loop

Middle tier: local synchronisation- involves 2 cells communicating with eachother (but that’s all i can decipher)

Upper tier: global control of slowing and arrest- results in elongation of A/P axis

37
Q

What TFs cycle in PSM in all species?

A

The expression of Hes/Her transcription factors, effectors of Notch signalling, cycle in PSM in all species

38
Q

Explain the single cell genetic oscillators: e.g. hes/her

A

Single cell genetic oscillators.
(A) Single-cell oscillator- gene products repress gene activity. This negative-feedback loop involves a sequence of steps. The Her/Hes gene is transcribed with a basal rate and mRNA is transported from the nucleus and translated. Proteins are transported back into the nucleus where they dimerize to form a transcriptional repressor. This repressor accumulates and binds the gene promoter to inhibit gene expression. Finally, when gene products (mRNA, protein, dimer) decay, the gene repression is released and the cycle can start over again.
Oscillations of mRNA and protein concentrations in the single cell oscillator.

39
Q

What proteins modify Notch signalling?

A

FRINGE :) :) :) e.g. lunatic

40
Q

What cyclic genes are involved in somitogenesis?

of-course, none of this is well understood

A

Cyclic genes belonging to the Notch and FGF pathways oscillate in opposite phase to cyclic genes of the Wnt pathway. A large number of the cyclic genes are involved in negative feedback loops. The basic circuitry of the three signalling pathways is represented.

All 3 pathways influence expression of Tbox genes e.g. Tbx6

41
Q

Describe local synchronization through intercellular communication in the segmentation clock:

A

How neighboring oscillating cells send and receive signals via the Delta-Notch pathway:

The genes that encode the Delta ligands are repressed by the same factors that control the single-cell oscillator feedback loop.

The Delta gene is transcribed and the mRNA exported to the cytoplasm. The mRNA is translated, and the protein undergoes post-translational modifications before becoming an active ligand for Notch receptors on the neighboring cell.

Upon ligand/receptor binding, the Notch intracellular domain (NICD) is proteolytically cleaved from the Notch receptor of the neighboring cell and translocates to the nucleus, where it positively regulates the transcription of cyclic genes, such as the Hes/Her gene.

Notch signaling is not required for basal Hes/Her gene transcription. The details of the feedback loop of single-cell oscillator are dimmed to highlight coupling in this figure. Pre-somitic mesoderm cells communicate with multiple neighbors, effectively sitting in a 3D lattice of mobile coupled oscillators.

42
Q

What is expressed in a pulsatile manner in the causal PSM and how do they act?

A

Notch and DLL

Notch protein precedes DLL

Notch translated and translocates to cell membrane

Notch & DLL at cell membrane = activation

Activation = NICD for Notch effectors, while DLL endocytosed

43
Q

What holds cells in the presomitic state? (part of the wavefront trigger)

A

A gradient of FGF8 protein, formed by mRNA instability.

44
Q

Describe the “wavefront” or gradient threshold

A

FGF & Wnt gradients similar, but produced by RNA and protein decay respectively

Cells leaving the tail bud stop de novo production of Wnt3a protein, so levels drop with time

When a threshold level is reached, cycling stops, and a cell is ready to become part of a somite

FGF may enhance Wnt activity, through Akt & Gsk3beta (sexy)

A Retinoic Acid gradient, formed by RALDH2, is in the opposite direction and antagonizes FGF

45
Q

What positions the determination front?

A

Antagonistic gradients of FGF/Wnt signalling and RA signalling

46
Q

What happens as the embryo extends posteriorly?

A

The determination front moves caudally

47
Q

What happens to cells that reach the determination front ?

A

They are exposed to the periodic clock signal, initiating the segmentation program by repressing Tbox genes and activating simultaneously expression of genes such as Mesp2 in a stripe domain that prefigures the future segment. This establishes the segmental pattern of the presumptive somites.

48
Q

Describe global gradients and then teach me xx

A

Global gradients control slowing and arrest of oscillating cells.

An elongating vertebrate axis showing cyclic gene expression patterns in blue/white and arrested segments and somites (solid boundaries).

Gradients of fibroblast growth factor (FGF) and Wnt (brown) span the tissue from the posterior. An opposing shorter-range retinoic acid (RA) gradient expands from the recently formed somites. The actual shape of these gradients is not known.

Sustained high-frequency oscillations are observed in the posterior region of the tissue. Oscillators gradually slow down as they approach the wavefront of arrest.

The panel on the left shows the different stages that single-cell oscillators undergo as they traverse the tissue. The right panel highlights the maturation program of pre-somitic mesoderm cells, running in parallel to segment length specification controlled by the clock.

49
Q

What happens when a group of cells at the right phase of the oscillating cycle hits the wavefront of FGF/Wnt/RA?

A

Cycling stops and the cells are induced to express Mesp2, which requires Tbx6 expression.
It is Mesp2, interacting with Tbx6 and residual Notch NICD, that sets the boundary for somite border formation

50
Q

What does Notch coordinate?

A

cyclic expression among PSM cells, synchronizing the clock and the spread of expression

51
Q

What does the Wnt, FGF and RA threshold represent?

A

Represents the wavefront with Wnt3a

High levels (above threshold): clock on
Low levels (below threshold): clock off
52
Q

What happens to cells at the correct phase of cycling?

A

Cells at the correct phase of cycling are competent to respond to the wavefront, switching on Mesp2 and stopping cycling

53
Q

What do Mesp2, Tbx6 and Notch do?

A

Mesp2, Tbx6 and Notch interact to promote somite border formation and cranio-caudal somite compartments

54
Q

In the WT, what does RA do?

A

Prevents PSM lateralization

55
Q

What happens in raldh2 -/-?

A

lateralization and asymmetric segmentation

56
Q

What does Mutation of Human Orthologs of the Segmentation Clock Genes Leads to ?

A

Congential scoliosis

57
Q

Name some dull, annoying Human mutations

A

Spondylocostal dysostoses
Multiple vertebral segmentation defects
Often with rib defects

DLL3 (Bulman et al, 2003)
Notch ligand

LFNG (Sparrow et al, 2006)
Notch modulator

MESP2 (Whittock et al 2004)

No1cares (Khadija et al 2017)

D&D (7 decks)

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