Deck 7: Wiring of the Nervous System

Question 1

What effects would you expect to see on the sizes of various areas of the telencephalon-primary visual cortex, primary somatosensory cortex, and frontal/motor cortex-if Wnt signaling were inhibited during anteroposterior patterning of the neural tube?

Answer 1

BMPs/Wnt signaling promotes expression of Emx2, which in turn leads to differentiation of posterior structures such as primary visual cortex (V1). Reducing BMP/Wnt signaling should lead to an expansion of anterior structures such as primary somatosensory cortex (S1) and frontal/motor cortex (F/M) at the expense of primary visual cortex, similar to an Emx2 knockout.

Question 2

If a mutation were to occur to disrupt the localization of ankyrinG, such that this protein became distributed throughout the Purkinje cell body and axon, what phenotype would you expect? Briefly explain your reasoning, assuming that the mutation does not disrupt interactions between ankyrinG and neurofascin.

Answer 2

Neurofascin would still associate with the ankyrinG, causing it to be diffusely distributed and resulting in the overshooting and abnormal branching of basket cell axon terminals.

Question 3

What might you expect to observe if multiple neurons were experimentally manipulated to express exactly the same combination of Dscam exons? Briefly explain your reasoning.

Answer 3

Perhaps counterintuitively, homotypic binding between identical Dscam proteins initiates an intracellular cascade that results in mutual repulsion. Therefore, even neurons for which processes normally overlap would be expected to avoid each other.

Question 4

The expression of neuroligins or neurexins in cultured nonneuronal cells demonstrates that these molecules are sufficient to induce presynaptic specializations in mouse hippocampal neurons in vitro. Rare mutations in neuroglian and neurexin genes have been associated with familial autism spectrum disorders. However, even mice lacking all three neuroligin genes still have the normal number of synapses. Propose some possible explanations to reconcile these findings and suggest some experiments that could be performed to distinguish between them.

Question 5

Expressing Lin44 more anteriorly also expands the localization of its receptor, Lin17 (Fz), towards the anterior. What is the expected DA9 motor neuron phenotype?

Question 6

The loss of Numb in the Drosophila SOP lineage results in two IIa precursors and the production of extra hair and socket cells at the expense of neuron and sheath cells, while the overexpression of Numb results in extra neuron and sheath cells at the expense of hair and socket cells. Which cell type(s) does Notch activity specify?
(a) IIa precursor
(b) Socket cell
(c) Neuron
(d) Both a and b
(e) Both a and c

Question 7

Motor neurons 1 and 2 start out innervating the same number of muscle fibers in a neonatal mouse. If motor neuron 1 releases more acetylcholine in the first two weeks postpartum, ultimately:
(a) motor neuron 1 will innervate more muscle fibers.
(b) motor neuron 1 will have a thicker axon.
(c) motor neuron 1 will be activated prior to motor neuron 2 during muscle contraction.
(d) a and b
(e) a, b, and c

Question 8

Dendritic tiling in the vertebrate retina (mutual avoidance by different neurons of the same class) is regulated by:
(a) alternative splicing of Dscam.
(b) expression of different combinations of protocadherins.
(c) ephrins and Eph receptors.
(d) All of the above
(e) None of the above

Question 9

Which of the following are sufficient for synapse formation and maturation in cultured retinal ganglion cells?
(a) Astrocytes
(b) Thrombospondins
(c) None of the above
(c) Thrombospondins and glypicans
(d) a and c

Question 10

Axon pruning in Drosophila mushroom body neurons appears to share molecular mechanisms with:
(a) motor axon terminal refinement at the vertebrate neuromuscular junction.
(b) regulation of callosal projections by mammalian corticocortical projection neurons.
(c) elimination of distal fragments of mammalian axons severed by injury.
(d) ephrin-mediated repulsion in the vertebrate tectum/superior colliculus.
(e) None of the above

Question 11

In early dorsoventral patterning studies, researchers found that transplanting a notochord from another embryo was sufficient to induce the expression of floor plate markers and motor neuron markers in a chick embryonic spinal cord explant (Figure Q7-6). What are some experiment(s) that could provide evidence that Shh is the specific signal that is both necessary and sufficient for the induction of ventral cell fates such as motor neurons? Figure Q7-6

Question 12

In the ventral nerve cord of the Drosophila larva, each neuroblast (neural stem cell) divides repeatedly, regenerating itself and generating a transient ganglion mother cell with each division (Figure Q7-4). Each ganglion mother cell then divides to produce two daughter cells. At the end of this process, a full neuroblast lineage is composed of two different types of neurons, A and B, in approximately equal numbers. Figure Q7-4
A. How might these two distinct types of neurons be generated?
B. What are some experiments that could be performed to test this hypothesis?

Question 13

Motor axons expressing EphBs:
(a) innervate muscles in the dorsal part of the limb.
(b) are attracted to ephrin-A.
(c) are located more medially in the spinal cord.
(d) also express the transcription factor Lim1.
(e) All of the above

Question 14

Various concentrations of Shh along the dorsoventral axis serve to activate or repress several transcription factors which then act in combination to specify neural progenitor domains and, ultimately, neurons (Figure Q7-5). The spinal cord progenitor domain in which Pax6 and Nkx6.1, but not Irx3 or Nkx2.2, are expressed will give rise to: Figure Q7-5
(a) V3 interneurons.
(b) V2 interneurons.
(c) V1 interneurons.
(d) V0 interneurons.
(e) motor neurons.

Question 15

All of the following are found in dendrites but not axons except for:
(a) Golgi outposts.
(b) plus ends of microtubules.
(c) minus ends of microtubules.
(d) local protein synthesis.
(e) None of the above

Question 16

Injecting ³H thymidine into a pregnant mouse near the end of cortical neurogenesis will label cortical excitatory neurons in layer(s):
(a) L2/L3.
(b) L4.
(c) L5.
(d) L6.
(e) All of the above

Question 17

There are three Robo genes (Robo, Robo2, and Robo3) encoding receptors for Slit, which acts as a midline repellant. In homozygous Slit mutant embryos, all axons collapse at the midline, while in homozygous Robo mutant embryos, axons re-cross the midline, resulting in thinner longitudinal tracts and thicker commissures (Figure Q7-8). Figure Q7-8
What would you expect the ventral nerve cord phenotype of a triple Robo mutant (loss of function of all three Robo genes) to be? Briefly explain your reasoning.

Question 18

The clustering of acetylcholine receptors in the vertebrate neuromuscular junction requires all of the following except:
(a) agrin.
(b) LRP4.
(c) a muscle-specific receptor tyrosine kinase.
(d) innervating motor axons.
(e) None of the above

Question 19

The kinase LKB1 (Par4) was first identified in C. elegans as a factor required for asymmetric cell division/fate in the early embryo: PAR4 mutant cells divide symmetrically, resulting in early lethality. If the role of Par4 is similar in both contexts, what might you expect to observe by staining early C. elegans embryos with an antibody to this protein?

Question 20

The semaphorins are highly conserved axon guidance ligands with critical roles in nervous system development in both mammals and insects. It was recently reported that Sema1A can also function as a transmembrane receptor in reverse signaling to mediate photoreceptor axon-axon attraction in the developing Drosophila visual system. What kind of experimental result would be used to support a role in reverse signaling in the visual system?

Question 21

TrkB knockout mice die early in postnatal life due to an inability to feed.
A. In the current model for neurotrophin and receptor function, pro-neurotrophins have high affinity for p75NTR, while mature neurotrophins act through one or more Trk receptors. Based on Figure Q7-22, would you expect a BDNF knockout mouse to have a more or less severe phenotype than the TrkB knockout? Briefly explain your reasoning. Figure Q7-22
B. Now consider the observation that many, perhaps most, neurons that express TrkB also express TrkA or TrkC. How does this alter your prediction?
Assembly of Olfactory Circuits: How Do Neural Maps Form?

Question 22

When the P2 coding region is replaced by IRES-tau-lacZ alone, the pattern of expression in the epithelium is indistinguishable from wild type, but the axons wander through the outer nerve layer, failing to converge to any particular region or glomerulus, once they enter the olfactory bulb. What can be inferred from this experiment?

Question 23

Roger Sperry's chemoaffinity hypothesis presupposes that each neuron carries a unique 'ID tag' that allows it to make the appropriate connections. We estimate that the human brain is composed of about 10¹¹ neurons making 10¹⁴ synaptic connections, yet the human genome only contains about 20,000 protein-coding genes. Given that there are not enough genes to identify even a small fraction of these neurons, what strategies have evolved in order to achieve the enormous degree of wiring specificity required for normal nervous system function??

Question 24

Alternative splicing appears to be responsible for the unique specification of a huge number of possible connections by generating many variants of:
(a) transcription factors.
(b) cell-surface proteins.
(c) diffusible axon guidance cues.
(d) neurotrophic factors.
(e) kinases.

Question 25

Overexpressing a single isoform of Dscam in a small subset of projection neurons shifted their dendrites to a neighboring glomerulus. Unexpectedly, the axons of their partner (wild-type) ORNs also shifted to the new glomerulus. Thus, Dscam appears to play a similar role to that of:
(a) Sema1A.
(b) Sema2B.
(c) Ten-a or Ten-m.
(d) Caps.
(e) None of the above

Question 26

cAMP-signaling-deficient ORNs fail to express Nrp1 and mistarget to more anterior glomeruli. When transgenic ORNs express various versions of the β2-adrenergic receptor (Figure Q7-25), what should their relative levels of Nrp1 expression be, from lowest to highest? Figure Q7-25

Question 27

Maxillary palp ORN axons:
(a) are attracted to Sema2A/2B in the developing antennal lobe.
(b) are repulsed by Sema2A/2B in the developing antennal lobe.
(c) are repulsed by Sema1A expression in other maxillary palp ORN axons.
(d) are repulsed by Sema1A expression in antennal ORN axons.
(e) All of the above

Question 28

In a CNG knockout mouse:
(a) Kirrel2 levels should be high in all/most ORNs.
(b) EphA levels should be high in all/most ORNs.
(c) ORN axons of at least some classes should fail to converge on a single glomerulus.
(d) All of the above
(e) None of the above

Question 29

Which spatial map in the brain is a discrete rather than a continuous map?
(a) Gustatory map
(b) Somatosensory cortex
(c) Motor cortex
(d) Tonotopic map
(e) Visual map

Question 30

Which of the following would not increase the number of motor neurons or sympathetic neurons surviving in a chick explant?
(a) Addition of purified NGF
(b) Addition of NGF antiserum
(c) Transplantation of an extra limb bud
(d) Transplantation of a sarcoma expressing NGF
(e) None of the above

Question 31

Roughly half of the projection neurons generated by the dorsal neuroblast are Caps⁺ and roughly half are Caps^-. Based on this information and the pattern of Caps expression in projection neurons and their glomerular targets in flies:
(a) Caps level governs glomerular targeting along the dorsolateral-ventromedial axis.
(b) Caps level governs glomerular targeting along the anteroposterior axis.
(c) Caps level segregates dendrites that have targeted to similar positions along the axes.
(d) Caps level depends on neuroblast lineage.
(e) All of the above

Question 32

What phenotype should result from the overexpression of Sema1A in a fly projection neuron? Briefly explain your reasoning.

Question 33

In a G_olf knockout mouse, what phenotype would you expect to see in labeled P2 axons?