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Dorso-ventral patterning of the mouse limb: Lmx1b Carlos G. Arques and Cristina Claver a Mammalian genomes, such as those of mice and humans, contain at least 12 LIM ... – PowerPoint PPT presentation

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Title: Presentaci


1
Dorso-ventral patterning of the mouse limb Lmx1b
Carlos G. Arques and Cristina Clavería
2
The LIM homeodomain (LIM-HD) protein family
  • Mammalian genomes, such as those of mice and
    humans, contain at least 12 LIM homeodomain
    (LIM-HD) genes that encode key regulators of
    developmental pathways.
  • LIM homeodomain (LIM-HD) proteins are
    transcription factors that contain
  • - Two LIM protein/protein interaction domains,
    each of them binding two zinc ions to form a
    finger-like structure.
  • A DNA binding homeodomain.

DNA
PROTEIN
PROTEIN
3
Lmx1b protein
Lmx1b is a member of the LIM-HD family of
transcription factors that plays a variety of
roles during development to determine body
pattern in vertebrates and invertebrates. Dorso-ve
ntral limb patterning in vertebrates is thought
to be controlled by the Lmx1b protein, which is
expressed in a spatially and temporally
restricted manner along the dorso-ventral limb
axis.  
Schweizer et al., 2004
Lmx1b is expressed in multiple murine tissues,
including the developing limbs and eyes, the
kidneys, the brain, and in cranial mesenchyme.
4
Lmx1b null mouse displays dorsal-to-ventral
conversion of the limbs and a lack of the patella
and nails.
Chen et al., 1998
Lmx1b null mouse model mimics the human disease
associated with Lmx1b mutations, nail-patella
syndrome (NPS).
5
Nail-patella syndrome
6
Nail-patella syndrome
Nail-patella syndrome (NPS) is an autosomal
dominant disorder caused by heterozygous
mutations in Lmx1b. It is characterised by
developmental defects of dorsal limb structures,
the kidney, and the eye, manifested by nail
dysplasia, patellar abnormalities, elbow
dysplasia, iliac horns, nephropathy and
glaucoma. Missense mutations are concentrated
within the homeodomain and the LIM domains, with
frameshift and nonsense mutations more widely
distributed throughout the coding region.
7
Lmx1b protein conservation
8
LIM A
LIM B
149
Both LIM domains are highly conserved, although
they have diverged one from each other.
Pathologic mutations affect the most conserved
residues between LIM A and B domains.
9
LIM A
Pathologic mutations
Disruption of Zn-finger
LIM B
10
HOMEODOMAIN
253
Homeodomain is highly conserved along evolution.
Pathologic mutations affect conserved residues.
11
HOMEODOMAIN
Pathologic mutations
Disruption of DNA binding
12
Conclusions
  • As nail-patella syndrome (NPS) is an autosomal
    dominant disorder, Lmx1b mutants might be acting
    as (partial) dominant-negative proteins.
  • Pathologic mutations in LIM domains affect the
    most conserved residues between A and B domains,
    and all of them seem to disrupt the zinc finger
    structure. Interestingly, no pathologic mutations
    have been described in these domains not directly
    affecting the zinc finger structure.
  • Pathologic mutations in homeodomain affect the
    most conserved residues, and all of them seem to
    affect DNA binding.
  • Mutations in other regions do not seem to be
    pathologic, at least in heterozygosity.

13
How does Lmx1b domain get its shape in the mouse
limb?
14
Current model
15
LOGO plus multi-agent capabilities plus a
expanded graphical interface Kid-oriented or
not Free (as in free beer)
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Exploring alternative models of rostral-caudal
paatterning in the zebrafishh neurectoderm with
computer4 simulations Chitnis and Itoh Current
Opinion in Genetics Development 2004
20
Wnt7a drives Lmx1b expression in the dorsal
mesenchime Wnt7a is expressed in dorsal
ectoderm Is diffusion enough?
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Wnt7a gradient shape is not the observed Lmx1b
domain shape
23
Lmx1b expression does respond to wnt7a Lmx1b
promoter activation is all or nothing Frontier
between lmx1b and not lmx1b cells is a straight
line
24
Lmx1b expression does respond to wnt7a Lmx1b
promoter activation seems to be all or nothing
wnt7a exposure changes cell state? Frontier
between Lmx1b and not lmx1b cells is a straight
line different affinities between lmx1b and not
Lmx1b cells?
25
Lmx1b expression does respond to wnt7a Lmx1b
promoter activation is all or nothing wnt7a
exposure changes cell state? Frontier between
lmx1b and not lmx1b cells is a straight line
different affinities between lmx1b and not Lmx1b
cells?
MODELExposure to high concentrations of wn7a
changes cells to lmx1b expressing state Lmx1b on
state is maintained in the absence of wnt7a Lmx1b
on state conffers special affinity for other
lmx1b expressing cells
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Affinity-driven reshaping of Lmx1b domain allows
other cells to enter the high wnt7a region and
become new Lmx1b-expressing cells
28
Finally, the system stops itself achieving the
expected domain shape
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Conclusions This model could explain what is
observed It predicts something (is
falsable) Would these be compartments?
(scholastic) Netlogo can be an useful tool
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