The weaver (wv) gene (GIRK2) is a member of the G-protein-gated inwardly rectifying potassium (GIRK) channel family, known effectors in the signal transduction pathway of neurotransmitters such as acetylcholine, dopamine, opioid peptides, and substance P in modulation of neurotransmitter release and neuronal excitability. GIRK2 immunoreactivity is found in but not limited to brain regions known to be affected in wv mice, such as the cerebellar granule cells and dopaminergic neurons in the substantia nigra pars compacta. It is also observed in the ventral tegmental area, hippocampus, cerebral cortex, and thalamus. GIRK2 and GIRK1, a related family member, have overlapping yet distinct distributions in rat and mouse brains. In regions where both channel proteins are expressed, such as the cerebral cortex, hippocampus, and cerebellum, they can be co-immunoprecipitated, indicating that they interact to form heteromeric channels in vivo. In the brain of the wv mouse, GIRK2 expression is decreased dramatically. In regions where GIRK1 and GIRK2 distributions overlap, both GIRK1 and GIRK2 expressions are severely disrupted, probably because of their co-assembly. The expression patterns of these GIRK channel subunits provide a basis for consideration of the machinery for neuronal signaling as well as the differential effects of the wv mutation in various neurons.

https://www.jneurosci.org/content/jneuro/16/22/7137.full.pdf

Heteromultimerization of G-Protein-Gated Inwardly Rectifying K+ Channel Proteins GIRK1 and GIRK2 and Their Altered Expression in weaver Brain

The midbrain of the adult homozygous weaver (wv/wv) mouse is notable for a reduction in the numbers of dopamine-containing cells in the substantia nigra (A9) and the retrorubral nucleus (A8). We have determined that the reduction in tyrosine hydroxylase (TH)-positive neurons in the ventral midbrain of the weaver is attributable to the loss of neurons after postnatal day 7 (P7). Because the number and spatial distribution of TH-positive mesencephalic neurons in wv/wv, heterozygous weavers (+/wv), and wild-type mice are not significantly different on P7, we conclude that the early developmental steps of proliferation and migration have taken place normally in the mutant. Although numbers and distribution of cells are normal in the wv/wv on P7, the appearance of the TH-stained ventral midbrain is abnormal because of the paucity of TH-stained dendritic processes. The ventrally extending TH-positive dendrites are largely absent in the young wv/wv. The wv/wv also can be distinguished from both homozygous normal (+/+) and wv/wv littermates on P7 based on the appearance of dendrites that are more numerous than in the wv/wv but thin, disorganized, and sparse compared with +/+. Most cell death seems to take place in wv/wv before P21. However, at least one subset of dopamine-containing neurons disappears later. The zone of densely packed TH-positive neurons in the substantia nigra that is likely to be the origin of innervation to striosomes in the caudoputamen disappears between P21 and adulthood. Despite the early pathology evident in the mesencephalic dopamine- producing neurons of the +/wv, no evidence for cell death was observed there even in the oldest +/wv weavers studied.

https://www.jneurosci.org/content/jneuro/16/5/1819.full.pdf

Cell death in the midbrain of the murine mutation weaver

Identification of the weaver mouse mutation: the end of the beginning.

Neuronal death affects selectively granule cell precursors of the cerebellum and the dopaminergic neurons of midbrain in the weaver mutant mouse. The weaver phenotype is associated with a missense mutation in the gene coding for the GIRK2 potassium channel, which results in chronic depolarization. Using DNA gel electrophoresis, electron microscopy (EM), the in situ end-labeling (ISEL) technique at the light and EM level, and immunohistochemistry for apoptosis-related proteins c-Jun and proliferating cell nuclear antigen (PCNA), we have investigated the mechanisms of cell death in cerebellum and substantia nigra. Between postnatal day P1 and P21, in the external germinal layer of the cerebellum, most degenerating granule cell precursors were found to aggregate to form clusters. Degenerating cells exhibited strong nuclear staining for ISEL, c-Jun, and PCNA and had a typical apoptotic morphology by EM. Increased c-Jun and ISEL staining were also occasionally seen in Purkinje cells. Between P14 and P21, when dopaminergic neurons start to degenerate, staining for ISEL, c-Jun, and PCNA in weaver substantia nigra was the same as in controls. By EM, however, we found only in weaver mice numerous dopaminergic cells that showed extensive vacuolar and autophagic changes of cytoplasm, preservation of membrane and organelle integrity, and absence of chromatin condensation or DNA fragmentation by EM-ISEL. The combination of vacuolar and autophagic changes identifies a novel type of non-necrotic, nonapoptotic cell death. After biochemical analysis of DNA, a clear-cut laddering, suggestive of oligonucleosomal fragmentation, was present in samples from weaver cerebellum. Cell death diversity appears to be influenced by specific features of target cells. These findings may be relevant for understanding the mechanisms of cell death in neurodegenerative diseases.

Diverse cell death pathways result from a single missense mutation in weaver mouse.

Cell death during development of testis and cerebellum in the mutant mouse weaver.

The pathologic phenotype of the testis in both prepuberal and postpuberal male weaver mutant mice was studied by light microscopy. Morphometric analysis of seminiferous tubules was carried out. Epididymal fluid was examined for the presence of spermatozoa. The seminiferous tubules of 21-day-old prepuberal weaver mutant mice lacked patent lumina and had more degenerated cells than control mice. Fifty-six day-old weaver mutants had many germinal epithelial cells located within the adluminal compartment that were in advanced stages of degeneration. Round spermatids were enlarged and multinucleated. Round spermatids and spermatocytes had sloughed into the lumen. Compared to control mice, elongated spermatids were seen less frequently. In older weaver mice, the degenerative process involved germ cells in both the adluminal and basal compartments. In 143- and 226- day-old weaver mutants, the Sertoli cells were atrophic. Diameters of seminiferous tubules in weaver mice were significantly reduced when compared to control mice. Sperm were either absent or very low in number in the epididymal fluid of postpuberal weaver mice. We conclude that spermatogenesis is abnormal in male weaver mutant mice. The testicular phenotype is characterized by a degenerative process that affects both germ cells and supporting cells.

Hypospermatogenesis is the Cause of Infertility in the Male Weaver Mutant Mouse

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Hypospermatogenesis is the Cause of Infertility in the Male Weaver Mutant Mouse