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Mice with the weaver mutation exhibit an uneven weave to their gait, ataxia, mild locomotor hyperactivity and, occasionally, tonic-clonic seizures. A single amino acid mutation in a G-protein coupled, inwardly rectifying K+ channel,
GIRK2, gives rise to the symptoms seen in the weaver mice. Two areas of the brain are primarily affected. Cerebellar
granule cell neurons die soon after birth and dopaminergic neurons are severely depleted in the substantia nigra. In
this article we review recent studies of wild-type and mutant GIRK channels found in native cells or introduced into
expression systems. We also review two models that explain some of the details leading to the neuronal cell death
observed in weaver mice.
Keywords:
GIRK K channel resting Ca2 cell death
Weaver phenotype
Throughout the last four decades, mutant mice have
been utilized as models to study neurological disorders,
neuronal degeneration and pathology. Spontaneous
mutations have given rise to distinctive phenotypes with
descriptive names such as staggerer, tottering, lurcher, and
shiverer. Many of these phenotypes are the result of a
pleiotropic mutation in which a single gene has multiple
and complicated effects on various cell types during
developmental and adult stages of the animal. One such
mutation is the weaver mutation, an inherited autosomal
recessive disease.12 The weaver mouse was initially
described as having an uneven weave to its gait and
ataxia due to cerebellar abnormalities.3 Later studies
reported that the weaver mouse also exhibits mild locomotor hyperactivity,4 male sterility5 and, occasionally,
tonic-clonic seizures.6
The most prevalent phenotype of the weaver mutation
involves cell death in the central nervous system that
produces a range of neurological dysfunctions. Two
regions of the central nervous system are predominately
affected. In the cerebellum, granule cell neurons die
soon after birth as they fail to differentiate and migrate
into the internal granule cell layer.7 This failure to
migrate appropriately led workers in the eld to postulate that the weaver mutation involved defects in
neuron-glia interactions or other molecular signals
typical of migrating and developing neurons.810 In
mutant mice, large numbers of granule cells are lost2,11
as well as lesser numbers of Purkinje cells12 and neurons
in the deep nuclei of the cerebellum13 producing the
prominent ataxia characteristic of these animals. There
is severe depletion of tyrosine hydroxylase-positive
(dopaminergic) neurons in the substantia nigra resulting
in alterations in locomotion.4,1415 In addition, there are
morphological abnormalities in the hippocampus that
may underlie the seizures.16
In the weaver mouse, the main defect outside of the
central nervous system is reduction in spermatogenesis.
There is decreased sperm motility and degenerative
changes in both mature spermatids and Sertoli cells.17
These defects lead to infertility in male but not female
weaver mouse.5,18
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AB Harkins, AP Fox
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AB Harkins, AP Fox
Purkinje neurons express inwardly rectifying K+ currents.81 Because GIRK2 expression does not exhibit any
gradient through the cerebellum,55 there may be additional environmental and/or genetic factors that inuence cell death. This idea is supported by experiments
in which weaver precursor granule cells were rescued
from cell death when mixed with wild-type cells.88 After
the granule cells were mixed, weaver granule cells
extended neurites and migrated suggesting that the premigratory granule cells responded to a local signal and
continued to differentiate.88 In vivo, weaver granule cells
are also rescued from death by environmental cues
following implantation of a wild-type granule cell suspension.10 The mechanisms contributing to the weaver
phenotype could also underlie the apoptotic cell death
and reduced migration of some, but not all granule cell
neurons, and the differential effects on other GIRK2
expressing neurons throughout the brain.
Conclusion
Although the specic mechanism underlying the GIRK2
defect in the weaver mouse is still not resolved, what has
become clear is that certain populations of neurons are
much more susceptible to the defect than are others. In
the granule cells of the cerebellum, both differentiation
and maturation are affected by the genetic defect.
Granule cell neurons die soon after birth as they fail to
differentiate and migrate into the internal granule cell
layer. Interestingly, the cell death observed in Purkinje
neurons that also express the channels is more modest.
Thus, identication of a point mutation in the
GIRK2wv channel as the causative agent leading to
cell death in specic neuronal populations within
both the substantia nigra and cerebellum has
underscored the critical role these channels play
in normal central nervous system development and
function.21,23,60,63,67,69,8991
Acknowledgement
We are thankful to Dr Lisa Won for reading the manuscript.
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