Lecture 10
• Types of lineage mutants
• Lateral inhibition in C. elegans
• Induction in C. elegans
Mutant names and origins
• Most isolated in general mutant screens
•
•
•
•
•
unc Uncoordinated
dpy Dumpy short and fat
lin lineage abnormal
egl egg laying
let lethal
Mutant names and origins
unc-93 (e1400)
Phenotypic class
ie screen isolated in
Complementation
group
lin-22(n372)
allele
Cell lineage mutants
• Canonical cell lineage
• Stem cell like mutant lineages
• Homeotic mutant lineages
• Heterochronic mutant lineages
Canonical cell lineage
Horvitz The Nematode C. elegans 1988
Canonical cell lineage
A
B
C
Horvitz The Nematode C. elegans 1988
Canonical cell mutant lineages
A
B
wild-type
C
A
B
A
B
B
A
Canonical cell mutant lineages
A
B
A
B
wild-type
C
Regeneration of
the mother cell
fate: stem cell like
B
B
A
A
Stem cell like mutant lineages
Horvitz The Nematode C. elegans 1988
Canonical cell mutant lineages
A
B
A
B
B
wild-type
C
Sisters have
the same
fate:
homeotic
A
B
A
Homeotic transformation
The transformation of one body part into
the likeness of another
Antennapedia can be misexpressed either by spontaneous
mutation or by genetic engineering.
+
Antp
ry
hsp
Antenna to second leg transformation
Canonical cell mutant lineages
A
B
A
B
B
wild-type
C
Sisters have
the same
fate:
homeotic
A
B
A
Cell lineage homeotic transformation
Horvitz The Nematode C. elegans 1988
Homeotic transformation of several lineages
Horvitz The Nematode C. elegans 1988
Heterochronic genes
Slack and Ruvkun Annu. Rev. Genet. 31, 611
Heterochronic genes
Slack and Ruvkun Annu. Rev. Genet. 31, 611
Heterochronic genes
Precious
development of
L2 lineage
Slack and Ruvkun Annu. Rev. Genet. 31, 611
Heterochronic genes
Suppression of L2
lineage and
replacement with L1
lineage.
Slack and Ruvkun Annu. Rev. Genet. 31, 611
Heterochronic genes
wt
lin14l
lin14gf
f
L1
ON
OFF
ON
OFF OFF
ON
lin-14 activity
L2
Heterochronic genes
Slack and Ruvkun Annu. Rev. Genet. 31, 611
Heterochronic genes
Slack and Ruvkun Annu. Rev. Genet. 31, 611
Heterochronic genes
lin-4
lin-14
Heterochronic genes
lin-14 encodes a nuclear protein
lin-4 encodes a non-coding RNA
a micro-RNA-the first found
Heterochronic genes
lin-4 RNA base pairs with the lin-14 3’ UTR
In lin-14gf mutants the lin-4 binding sites
are deleted.
Slack and Ruvkun Annu. Rev. Genet. 31, 611
Heterochronic genes
Levels
lin-14 mRNA
L1
L2
L3
L4
Levels
Heterochronic genes
lin-14 protein
L1
L2
L3
L4
Levels
Heterochronic genes
lin-14 protein
lin-4 micRNA
L1
L2
L3
L4
Temporal Morphogen hypothesis
Kalthoff Analysis of Biological development 2nd ed
Lateral inhibition
Order arising from nothing: an emergent property
Gilbert Developmental Biology 5th ed
Lateral inhibition
Order arising from nothing: an emergent property
Gilbert Developmental Biology 5th ed
Anchor cell/ Ventral uterine cell equivalence group
Individual A
Z1.ppp
AC
Z4.aaa
VU
Individual B
Z1.ppp
Z4.aaa
VU
AC
Model for AC/VU decision
Gilbert Developmental Biology 5th ed
Model for AC/VU decision
Equivalent signaling
Gilbert Developmental Biology 5th ed
Model for AC/VU decision
Stochastic difference
in signaling
Gilbert Developmental Biology 5th ed
Model for AC/VU decision
Differential expression
of receptor and ligand
Gilbert Developmental Biology 5th ed
Model for AC/VU decision
Determined cell fates
Gilbert Developmental Biology 5th ed
Genetic analysis of lateral inhibition
gf
lin-12
+(wt)
lin-12
lf
lin-12
Z1.ppp
Z4.aaa
VU
VU
AC/VU
AC/VU
AC
AC
Mosaic analysis in C. elegans
ncl-1+ lin-12+
ncl-1
qDp3
lin-12
qDp3 is a free duplication that is
mitotically unstable and is lost
forming clones of ncl-1 lin-12 cells
Mosaic analysis in C. elegans
ncl-1
+
ncl-1
In ncl-1 cells, the nucleolus is large.
Mosaic analysis in C. elegans
ncl-1 lin-12 cell
Seydoux and Greenwald Cell 57, 1237
Mosaic analysis in C. elegans
Individual A
Z1.ppp
Individual B
Z4.aaa
lin-12
lin-12
AC
VU
+
Z1.ppp
lin-12
VU
Z4.aaa
+
lin-12
AC
Mosaic analysis in C. elegans
Individual A
Z1.ppp
Individual B
Z4.aaa
lin-12
lin-12
AC
VU
+
Z1.ppp
lin-12
VU
Z4.aaa
+
lin-12
AC
Lin-12 activity is required in the VU cell
Model for AC/VU decision
Gilbert Developmental Biology 5th ed
Expression of Lin-12 protein
Precommitment
Committed
Levitan and Greenwald Development 125, 3101
Induction of the vulva in C. elegans
Vulva equivalence group
Wormbase
Induction of the vulva in C. elegans
Horvitz and Sternberg Nature 351, 535
Induction of the vulva in C. elegans
Horvitz and Sternberg Nature 351, 535
Induction of the vulva in C. elegans
Horvitz and Sternberg Nature 351, 535
Induction of the vulva in C. elegans
Horvitz and Sternberg Nature 351, 535
Induction of the vulva in C. elegans
Horvitz and Sternberg Nature 351, 535
Induction of the vulva in C. elegans
Horvitz and Sternberg Nature 351, 535
Induction of the vulva in C. elegans
wild-type
Vulvaless Vul
Multivulva Muv
Ferguson and Horvitz Genetics 110, 17
Induction of the vulva in C. elegans
Ferguson et al. Nature 326, 259
Induction of the vulva in C. elegans
Wormbase
Lin-3 a morphogen?
At high concentration of Lin-3:
1° fate
At medium concentration of Lin-3:
2° fate
At low concentration of Lin-3:
3° fate