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Developmental Neurobiology > Spinal Cord Patterning > Flashcards

Spinal Cord Patterning Flashcards

1
Q

how can the process of specifying motor neurons be divided into three stages?

A
  • the specification of gent motor neuron identity leads to the generation of motor neurons in the appropriate position in the spinal cord
  • the somas of the functionally related groups of motor neurons that are destined to share common projecion targets settle in longitudinally orientated columns in the spinal cord and their axons project towards the target region
  • the cell bodies of motor neurons that innervate the same muscle form clusters known as motor pools and both pre and post synaptic connections are made
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2
Q

is neurogenesis in the spinal cord symmetrical?

A

yes, it proceeds with bilateral symmetry

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3
Q

where in the spinal cord are motor neurons produced?

A

ventrally

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4
Q

why is the ventricular zone thicker in the dorsal region?

A

the motor neurons are generated before the dorsal neurons (ventrally) resulting in a reduction in the number of ventral neuroblasts. so the VZ is thicker at the dorsal midline that ar the ventral midline.

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5
Q

what does the floor plate go on to form?

A

glial cells

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6
Q

how was it first uncovered that notochord patterned floor plate? (2)

A

in mutants that have two notochord, two floor platers form

- grafting an ectopic nothocrd next to the neural tube resulted in the induction of floor plate adjacent to the graft

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7
Q

how was it shown that floor plate and notochord was required for motor neuron development? (2)

A

removal of floor plate and notochord abrogated the formation of motor neuron differentiation
- ectopic floor plate could induce motor neuron fate

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8
Q

what is the argument against floor plate requiring notochord signals?

A

there is evidence that floor plate cells are derived from axial mesodermal cells and they are inserted into th neural tube as hensens node regresses. This suggested that floor plate cells have shared lineage with notochord and raise the possibility that notochord signals are not needed for floor plate induction

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9
Q

how was it consolidated that signals from the notochord could induce floor plate and motor neurons? what was the general theory that derived from this?

A
  • explants of the neural plate could be cultured next to neural plate tissue in vitro.
  • this showed that direct contact was required for floor plate to be induced by notochord but that a diffusible signal was only required for motor neuron differentiation. from this it was suggested that floor plate is induced by notochord and then then the floor plate takes on the same traits as notochord to induce motor neurons
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10
Q

what first suggested that the induction of the floor plate and motor neurons was down to a concentration gradient?

A

there was a constant spatial relationship between the floor plate and motor neurons that were induced via ectopic notochord.

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11
Q

how was shh first proposed to be the morphogen acting? (2)

A
  • it was found to be expressed in the floor plate and the notochord.
  • its ectopic expression could induce ventral cell types in vitro and in vivo
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12
Q

describe an experiment which should shh was able to act like the notochord

A

cell that were transacted with a Shh expression vector and placed in contact with neural plate explants were able to induce the differentiation of floor plate and motor neurones

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13
Q

how was it shown that different levels of shh was required for either the floor plate or motor neuron fate?

A

culture the neural tube and apply different concentrations of shh- see different fate

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14
Q

how is it thought that cells respond to shh signalling?

A

transcription factors expressed in the ventral cells act as intermediaries in the interpretation of graded shh signalling. these TFsa re divided into two classes (I and II) the expression of class I is repressed at certain levels of shh and the expression of class II is activated by shh

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15
Q

what does the relationship of class I and class II TFs in the ventral cells mean about their expression pattern along the DV axis?

A 
class I is inhibited by certain levels of shh so its ventral limit of expression in determined by shh
class II is activated by shh so its dorsal limit limit of expresso i defined by graded shh
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16
Q

how are the defined borders of the class I and class II TFs defined?

A

class I and class I mutually repress ech other

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17
Q

what is the consequence of the class I and class II TFs that are mutually repressive?

A
  • creates a mechanism by which an shh gradient can be converted into discrete, all r nothing changes in been expression
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18
Q

what does the way in which shh is translated into different gene expression domains in the neural tube resemble?

A

the patterning of the AP axis in flies

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19
Q

how many cellular subtypes are created fem the interaction between 4 TFs in the ventral region of the neural tube?

A

5

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20
Q

what are the 5 class I Tfs?

A

pax6 and dbx 2, dbx1,pax7, irx3

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21
Q

what are the class II tfs?

A

nkx2.2 and nkx6.1

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22
Q

what are the pairings of the class I and class II Tfs?

A

pax6 and nkx2.2 , dbx2 and nk6.1

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23
Q

what are the 5 neuronal subtypes that are created?

A

V0, V1, V1, MN and V3

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24
Q

what are the majority of class I and class I TFs?

A

transcritional repressors- repress dorsal genes (like BMP being inhibited)

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25
Q

which cell type domain forms Motor neurone?

A

MN

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26
Q

the combination of action of which three TFs is needed for MN formation?

A

nkx6.1, nk2.2 and irx3 - ventrally Nkx2.2 and drosally irx3 ensures that motor neurone induction is not initiated outside of this region. Nkx6.2 activates the expression of olig2 and MNR2

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27
Q

what does nkx6.6 activate in order to induce motor neurone fate?

A

olig2 and MNR2-

28
Q

what is this patterning of the neural tube in vertebrates the equivalent to?

A

the patterning of the checkerboard in the ventral neural cord of the fly

29
Q

how is shh signalling thought to activate the expression of class I and class II TFs?

A

Gli proteins can act as both transcriptional repressors and transcriptional activators and an attractive mode suggests that shh signalling inhibits the transcriptional repressor activity and potentiates transcriptional activation.

30
Q

what experiment implicates Gli in shh mediated ventralisation?

A

The Gli class of zinc finger transcription factors appear to be key mediators of Shh signalling as repression of all Gli mediated transcription inhibits ventral neural tube patterning

31
Q

what is the role of BMP in shh mediated patterning?

A

the response of ventral neural progenitors to Shh seems to be influenced by BMP signalling. Exposure of neural plate explants to a fixed concentration of Shh in the presence of BMPs results in a ventral-to-dorsal shift in progenitor and neuronal subtype identity (Liem et al., 2000). Conversely, BMP inhibitory proteins ventralize the response of neural plate cells to a set Shh concentration (Liem et al., 2000). BMP signalling could therefore play a role in establishing a dorsal ventral patterning and may represent the source of positional information revealed in the Shh/Gli3 double mutant mice.

32
Q

how was it shown that motor axons are sorted depending on their area of projection?

A

using orthograde and retrograde tracing of motor axons

33
Q

how are the different MNs orientated in the spinal cord relative to where they project to?

A
  • axial muscles= medial subsolumn called the MMcm
  • more lateral to the above are the body wall MNs in the MMCl
  • more lateral still ar the MNs that project to the limb muscles in the LMC.
34
Q

what are the subsolumns of the LMC?

A

those that project dorsally (LMCl) or those that project ventrally (LCMm)

35
Q

how are the different functional columns within the MN region of the ventral spinal cord distinct?

A
  • different gene expression
36
Q

where along the spine is the MMCm column found?

A

along the entire spinal cord

37
Q

where along the spine is the LCM found?

A

only at the limb field level

38
Q

generally how are the different columns wihtn the spinal cord specified?

A

ignals derived from paraxial mesoderm control columnar subtype identity and indicated that this specification is an early event, occurring soon after the specification of motor neuron progenitors

39
Q

what does Olig2 activate?

A

MNR2 and lim3 which then activate HB9 and Isl1

40
Q

what do MNR2 and lim 3 activate?

A

HB9 and Isl1

41
Q

how can you visualise the expression of the different TFs in the ventral tube?

A

immunofluouresence

42
Q

what happens when you KO nk6.1?

A

you lose the motor neurone

43
Q

what happens if you over express nk6.1 in dorsal cells?

A

the dorsal cells produce ectopic MNs

44
Q

what is the keys factor that generates MN expression?

A

nkx6.1

45
Q

what do nkx2.2 and irx3 (that are expressed either side of nkx6.6) suppress?

A

olig2 which is required for MN fate

46
Q

what neurone are found in the dorsal region of the spinal cord?

A

commisural neurons, secondary sensory neurons, and their associated interneurons

47
Q

does floor plate secrete shh?

A

yes

48
Q

what is the role of RA in neural tube patterning?

A

it is secreted by the adjacent mesoderm adnc ontrols the conversion of neuroepithlail neuronal precusors to motor neurone

49
Q

what specifies the dorsal neuronal fates?

A

BMP from the roof plate-roof plate induced by epidermis

50
Q

what are the other 4 classes of neurone produced in the ventral nerve cord?

A

interneurons

51
Q

list the order in terms of low to high shh conc in which the class 1 TFs are suppressed

A

pax7, dbx1, dbx2, irx3, pax6

52
Q

is nkx6.1 or nix 2.2 activated at higher levels of shh?

A

nkx.2.2

53
Q

what type of factors the class I and class II factors?

A

homeobox TFs

54
Q

what is the temporal adaptation model of shh concentration gradient?

A

the duration of signal is also important as cells progressively become desensitised to shh signalling - different ambient concentrations of shh wouldd signal for different amounts of time such that the duration of signal is proportional to the concentration of signal

55
Q

how does the temporal adaptation model overcome a problem?

A
  • it overcomes the problem that a simple diffusion gradient would not be sufficient to set up a gradient because the extraellular concentrations of a diffusing molecule at any point change over time and its movement is affected by other extracellular molecules
56
Q

what is the family of proteins that is expressed differentially in the LMC vs MMcm ?

A

lim homeodomain family

57
Q

in the LIM, what is expressed in cells that settle in the lateral position vs medial position ?

A

lim1 vs isl1

58
Q

what is thought to be involved in the patterning of the columns of nerves?

A

FGF signals from the node and signals from the paraxial mesoderm

59
Q

what is the inside-out pattern of motor neuron differentiation?

A

earlier born neurons reside in the medial area and later born neurons reside in the lateral regions

60
Q

eventhough LCM neurons are found within the same column, and at the same point in the spinal cord, how is it that the dorsal and ventral neuronal populations are differentiated during development?

A

the dorsal neurons are differentiated later than the ventral ones - so lim1 is downregulated in these so they have a different fate

61
Q

how was shh shown to be necessary for ventral neural tube cell fate? (2)

A

the loss of ventral neural tube cell fates in embryos in which Shh signalling had been eliminated using either antibody blockade in vitro or by gene targetting in mouse

62
Q

how were shh levels shown to alter the expression of ventral neuronal subtypes?

A

the identification of molecular markers for additional ventral neuronal subtypes extended these obser- vations and it has become apparent that incremental 2 – 3 fold changes in Shh concentration generate at least five molecularly distinct classes of ventral neurons in addition to floor plate cells. The concentration of Shh necessary to induce each of these neuronal classes in vitro corresponds to its distance from the source of Shh in vivo. neurons generated in progressively more ventral regions of the neural tube require correspondingly higher Shh concentrations for their induction. Therefore, Shh appears to function in a graded manner to pattern the ventral neural tube, directing the position of generation and subtype identity of the neurons at defined concentration thresholds.

63
Q

how was it shown that shh functions directly at long-range to control ventral neural tube patterning?

A
  • it was originally thought that shh could act as short range to initiate the relay signals that would act tot pattern the neural tube
  • To test the range of Shh signalling in the neural tube a method of blocking the response of individual cells to Shh was devised by constructing a mutated form of the Hh receptor, Patched (Ptc). This mutant Ptc acted as a dominant inhibitor of Shh signalling even in the presence of Shh ligand (Briscoe et al., 2001). In ovo electroporation of the neural tube was used to produce mosaic unilateral expression of mutant Ptc result- ing in the blockade of Shh signalling in clusters of cells in the ventral neural tube. Analysis of the transfected neural tubes demonstrated inhibiting Shh signalling led to the cell- autonomous inhibition of the generation of motor neurons and other ventral neuronal classes arguing against signal relay models and indicating that Shh functions directly, at long-range to control ventral neural tube patterning.
64
Q

what does roof plate secrete?

A

BMP (4 and 7) and WNT

65
Q

what is the mediator of the BMP signals from the epidermis to induce roof plate?

A

Lmx1a

66
Q

what gene is expressed in the roof plate but not Neural crest cells?

A

lmx1a

67
Q

what is a theory about how the neural crest cells and roof plate are differentiated between?

A

there is an idea that initially all of the dorsal cells have migratory fate but that the roof plate cells lose it

Developmental Neurobiology (10 decks)

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