Direct correlation between Purkinje and granule cell number in the cerebella of lurcher chimeras and wild-type mice

Wetts, Richard; Herrup, Karl

doi:10.1016/0165-3806(83)90119-0

Cited by 133 publications

(70 citation statements)

References 26 publications

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“…4 F and J). This pattern corresponds to a general gradient laid down in the developing brain, whereby anterior regions develop marginally earlier than posterior ones, and is in keeping with the observation that anterior parts of the cerebellum are generally more susceptible to neurodegenerative processes, especially loss of Purkinje cells (36)(37)(38). At 28 weeks, Purkinje and granule cell loss as well as the extent of gliosis were no more severe than at 3 and 6 weeks (data not shown).…”

Section: Histopathology Of Tg L7dplsupporting

confidence: 60%

Transgene-driven expression of the Doppel protein in Purkinje cells causes Purkinje cell degeneration and motor impairment

Anderson

Rossi

Linehan

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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The Doppel (Dpl) and Prion (PrP) proteins show 25% sequence identity and share several structural features with only minor differences. Dpl shows a PrP-like fold of its C-terminal globular domain and lacks the flexible N-terminal tail. The physiological functions of both proteins are unknown. However, ubiquitous Dpl overexpression in the brain of PrP knockout mice correlated with ataxia and Purkinje cell degeneration in the cerebellum. Interestingly, a similar phenotype was reported in transgenic mice expressing an N-terminally truncated PrP (⌬PrP) in Purkinje cells by the L7 promoter (TgL7-⌬PrP). Coexpression of full-length PrP rescued both the neurological syndromes caused by either Dpl or ⌬PrP. To evaluate whether the two proteins caused cerebellar neurodegeneration by the same mechanism, we generated transgenic mice selectively expressing Dpl in Purkinje cells by the same L7 promoter. Such mice showed ataxia and Purkinje cell loss that depended on the level of Dpl expression. Interestingly, the effects of high levels of Dpl were not counterbalanced by the presence of two Prnp alleles. By contrast, PrP coexpression was sufficient to abrogate motor impairment and to delay the neurodegenerative process caused by moderate level of Dpl. A similar situation was reported for the corresponding TgL7-⌬PrP mice supporting the concept that Dpl and ⌬PrP cause cell death, possibly by interfering with a common signaling cascade essential for cell survival.

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Section: Histopathology Of Tg L7dplsupporting

confidence: 60%

Transgene-driven expression of the Doppel protein in Purkinje cells causes Purkinje cell degeneration and motor impairment

Anderson

Rossi

Linehan

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…4, F-H), whereas many TUNEL + granule cells were observed (not depicted). The apoptotic death of granule cells is likely to be induced by dying Purkinje cells as suggested by earlier fi ndings (26,27).…”

Section: Defi Ciency In Dicer and Mirnas Leads To Degeneration Of Purmentioning

confidence: 87%

Cerebellar neurodegeneration in the absence of microRNAs

Schaefer¹,

O’Carroll²,

Hillman³

et al. 2007

J Cell Biol

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The recently discovered potent role of microRNAs (miRNAs) in regulation of gene and protein expression suggests an important role for these small RNAs in regulation of various physiological processes. miRNAs are ‫-12ف‬nt-long noncoding RNAs that are processed from endogenously generated ‫-07ف‬nt-long hairpin structures by the RNase III enzyme Dicer. The nascent miRNA is incorporated into the RNA-induced silencing complex that mediates miRNA-dependent translational suppression or, in rare cases, cleavage of respective mRNA targets (for review see references 1-3). Ablation of the miRNA-generating enzyme Dicer revealed a requirement for miRNAs in development of immune cells (4-6), skin progenitors (7), and limb outgrowth (8). The predicted role of miRNAs in regulation of mammalian cell function has been underscored by fi ndings that show the ability of individual miRNAs to aff ect diff erentiation and function of cells of various lineages, including T cells (9) and cardiac myocytes (10, 11).Several lines of evidence indicate the possibility of an important role of miRNAs in neuronal cells. Compared with other organs, both mouse and human brain express an exceptionally diverse spectrum of distinct miRNAs (12-16). Furthermore, the existence of neuron-specifi c miRNAs argues in favor of their important role in neuronal diff erentiation and/or specialized functions. The involvement of miRNAs in neuronal diff erentiation is strongly supported by dynamic changes in miRNA expression during brain development (14,17,18). Moreover, the ability of neuron-specifi c miRNA miR-124a to suppress expression of nonneuronal genes in an in vitro cell system suggests an important role for miRNAs as regulators of neuronal differentiation (19). The signifi cance of miRNAs in neuronal physiology is also suggested by data that show miRNA involvement in dendritic spine formation and neurite outgrowth in vitro (20,21). In summary, although there is mounting evidence for important roles for miRNAs in neuron cell diff erentiation, their role in diff erentiated, postmitotic neurons has not been addressed.Using Purkinje cells as a model system to analyze the role of miRNAs in postmitotic neurons, we demonstrate an essential role for miRNAs in neuronal survival. We show that inactivation of Dicer leads to relatively rapid disappearance of Purkinje cell-expressed miRNAs,

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“…In fact, in preliminary studies, no changes of the adhesive behaviour of granule cells could be directly demonstrated in primary cultures from TAG/F3 mice (data not shown); however, the possibility cannot be excluded that more subtle effects may occur in vivo among contacting granule cells, resulting in a reduction of their adhesive strength. Alternatively, the effects on GC proliferation could depend upon changes in PC differentiation, which were evident as early as P0 in TAG/F3 mice, particularly since it is known that GC proliferation depends on PC-derived signals (Wetts and Herrup, 1983;Smeyne et al, 1995;Baader et al, 1998;Chomez et al, 2000;Dahmane and Ruiz i Altaba, 1999;Wechsler-Reya and Scott, 1999). However, since the TAX-1 promoter used for transgene generation is not expressed in PCs, it is likely that these changes are anyway initiated through contacts with F3/contactin-overexpressing GCs.…”

Section: F3/contactin Expression Affects Granule Cell Proliferationmentioning

confidence: 99%

Transgenic mice expressing F3/contactin from the TAG-1 promoter exhibit developmentally regulated changes in the differentiation of cerebellar neurons

Virgintino²,

et al. 2003

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F3/contactin (CNTN1) and TAG-1 (CNTN2) are closely related axonal glycoproteins that are differentially regulated during development. In the cerebellar cortex TAG-1 is expressed first as granule cell progenitors differentiate in the premigratory zone of the external germinal layer. However, as these cells begin radial migration, TAG-1 is replaced by F3/contactin. To address the significance of this differential regulation, we have generated transgenic mice in which F3/contactin expression is driven byTAG-1 gene regulatory sequences, which results in premature expression of F3/contactin in granule cells. These animals (TAG/F3mice) display a developmentally regulated cerebellar phenotype in which the size of the cerebellum is markedly reduced during the first two postnatal weeks but subsequently recovers. This is due in part to a reduction in the number of granule cells, most evident in the external germinal layer at postnatal day 3 and in the inner granular layer between postnatal days 8 and 11. The reduction in granule cell number is accompanied by a decrease in precursor granule cell proliferation at postnatal day 3, followed by an increase in the number of cycling cells at postnatal day 8. In the same developmental window the size of the molecular layer is markedly reduced and Purkinje cell dendrites fail to elaborate normally. These data are consistent with a model in which deployment of F3/contactin on granule cells affects proliferation and differentiation of these neurons as well as the differentiation of their synaptic partners, the Purkinje cells. Together,these findings indicate that precise spatio-temporal regulation of TAG-1 and F3/contactin expression is critical for normal cerebellar morphogenesis.

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Direct correlation between Purkinje and granule cell number in the cerebella of lurcher chimeras and wild-type mice

Cited by 133 publications

References 26 publications

Transgene-driven expression of the Doppel protein in Purkinje cells causes Purkinje cell degeneration and motor impairment

Transgene-driven expression of the Doppel protein in Purkinje cells causes Purkinje cell degeneration and motor impairment

Cerebellar neurodegeneration in the absence of microRNAs

Transgenic mice expressing F3/contactin from the TAG-1 promoter exhibit developmentally regulated changes in the differentiation of cerebellar neurons

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