Download Jan 18

• Last Lecture
– Molecular pathways to select a single
neuroblast from proneural cluster
Lect 5
• Today
– Neuroblast → neuron (or glia)
– D/V patterning
– Anterior/posterior patterning
Neuroblast formation in Drosophila
Prepatterning
Proneural
Clusters
Single Cells
selected to
become neurons
& inhibit
neighbours
Neurons
Specifying
neuronal type
Ganglion Mother CellII (GMCII)
Ganglion Mother CellI (GMCI)
Neuroblast
Dorsal-Ventral
Patterning genes
Proneural
genes
Neurogenic
genes
1
Asymmetric Cell Division leads to
generation of neurons
Neurons or glia
GMCI
NB
GMCI
GMCII
GMCI
GMCII
GMCIII
NB
NB
What controls NB vs GMC identity
• Neuroblast vs. GMC
– Asymmetric localization of prospero and
numb at cell division
• prospero and numb go into GMC and are excluded
from NB
• prospero and numb are important for maintaining
GMC fate, and repressing NB fate
• Mechanism involves actin cytoskeleton
NB
& prospero
• At cell division
– Numb and Prospero become localized to the
GMC
– Inscuteable orients the mitotic spindle
– Proteins such has Miranda, move along actin
cytoskeleton to opposite pole
– Miranda binds to Numb and Prospero
– Numb and Prospero specify GMC
• Numb inhinits Notch signalling pathway
2
CSN neuroblasts
PNS neurons
Prospero
Green = numb
Red = DNA
Actin
DNA
Spana & Doe, 1995
• Mutants of prospero
– Failure to express “GMC genes”
– Incorrect cell lineage
• Prospero also required for glial vs neural
lineage
– prospero can activate expression of glial cells
missing (gcm)
– gcm is a master regulator gene for glial cell fate
gcm-
glia
U
neurons
gcm+
3
Short Summary
•
Drosophila Neurogenesis
1.
2.
3.
4.
5.
6.
Dorsal ventral pattern (dpp, sog)
Establishing neurogenic region (SoxN)
Activation of proneural genes (A-SC)
Selection of neuroblast (Notch signaling)
Identity of GMC
Glial cell fate
•
How to get specific neurons
1. Dorsal / ventral patterns within the nervous
system
2. Anterior / posterior patterns
1b. D/V patterning of neural
tube
Dorsal
Neural tube
Neural plate
Ventral
Transcription factors in NB change over
time
1a – in flies, the GMCs inherit transcription
factor profile of the NB at the time of cell
division
mesoderm
notochord
Vertebrate embryo
4
D/V patterning of neural tube
Control
Remove Notochord
Extra Notochord
What is notochord signal?
Sonic Hedgehog
neurons
Floor plate
Text Fig 2.17
Implies a signal from notochord to neural tube
Jessell, 2000, Nature Reviews Genetics
• Sonic Hedgehog
– Secreted protein
Subtypes of interneurons
– Different concentrations of Shh induce different types
of neurons
– Shh regulates expression of 6 different transcription
factors based on concentration gradient
Motor neurons
interneurons
Jessell, 2000, Nature Reviews Genetics
– Combination of transcription factors defines which
type of neuron will develop
5
Fig 2.22
D/V patterning of neural tube
BMPs
Shh
+Shh
+BMP
+Shh
BMPs
Ventral
markers
Shh
Dorsal
markers
BMPs suppress Shh-induced ventral
• Antagonism of BMPs and Shh
– Opposing gradients control the dorsal ventral
polarity of the spinal cord and cell fates along
the D/V axis
• Shh
– Activates transcription factors that identify
unique groups of neurons
Shh
MNR2
ISL1
Motor neurons
6
How to get specific neurons
2. Anterior posterior postion
– Anterior posterior patterning
– Homeobox genes
– Combinatorial signaling
Anterior-Posterior Patterning
– In most animals the head looks different than
the tail!
– In most animals the body of the animal is
segmented
• Think spinal column / vertebrae
Bic
•
Again, look at patterning of Drosophila embryo
nanos
1. Gradients of Maternal Products in the egg
2. Gap genes
•
Kruppel
hunchback
because there are gaps in there expression pattern
Eve
ftz
3. Pair-rule genes
•
because expressed in pairs of segments
en
4. Segment polarity genes
•
Specify anterior / posterior boundaries of individual
segments
7
• Maternal genes
– define global A/P axis
• Gap genes
– subdivide embryo into broad regions
• Pair-rule genes
– broad stripes define an initial repeat of 2 segments
• Segment polarity genes
– Further subdivide segments into compartments
8