In vitro evidence that the reduction in mesencepalic dopaminergic neurons in the weaver heterozygote is not due to a failure in target cell interaction

Won, Lisa; Ghetti, Bernardino; Heller, Bárbara; Heller, Alfred

doi:10.1007/pl00005679

Cited by 9 publications

(8 citation statements)

References 34 publications

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“…Developmental abnormalities have been observed in cerebellum of weaver heterozygote animals ( wv/+ (Rakic & Sidman, 1973 a ; Smeyne & Goldowitz, 1989) even in embryos (Bayer et al 1996). Increased cell death has been observed in cerebellar neurons of the wv/+ animals (Willinger & Margolis, 1985; Wullner et al 1995) as well as in dopaminergic neurons of the mesencephalon (Verina et al 1997; Won et al 1997) but much less than that found in wv/wv animals. In part, the diminished cell death observed in wv/+ animals relative to wv/wv may be due to a gene dosage effect; the heterozygous cells presumably express less GIRK2 wv (Hess, 1996).…”

Section: Discussionmentioning

confidence: 89%

“…High levels of GIRK expression are found in the olfactory bulb, hippocampus, cortex, thalamus and cerebellum (Karschin et al 1996). Identification of the mutation in the GIRK2 wv channel as the causative agent leading to cell death in specific neuronal populations within the substantia nigra and cerebellum has underscored the important role these channels play in normal CNS functions across a broad range of systems (Kofuji et al 1996; Liao et al 1996; Navarro et al 1996; Slesinger et al 1996; Tong et al 1996; Won et al 1997). Although the exact mechanism by which the defect in GIRK2 wv leads to death is still unknown, several possible explanations have been proposed.…”

Section: Discussionmentioning

confidence: 99%

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Evidence of elevated intracellular calcium levels in weaver homozygote mice

Harkins

Dlouhy

Ghetti

et al. 2000

The Journal of Physiology

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In weaver (wv) mice, the substitution of a serine for a glycine (G156S) (Patil et al. 1995) alters the putative pore-forming H5 region (MacKinnon & Yellen, 1990) of the inwardly rectifying GIRK2 potassium channel and results in the loss of selectivity for K¤ ions, allowing Na¤ and Ca¥ ions to permeate into cells Navarro et al. 1996;Silverman et al. 1996;Slesinger et al. 1996;Tong et al. 1996). The wv mutation results in cell death in the central nervous system and testes producing a range of neurological dysfunctions and infertility in the male (Vogelweid et al. 1993;Patil et al. 1995;Kofuji et al. 1996;Liao et al. 1996;Navarro et al. 1996;Silverman et al. 1996;Slesinger et al. 1996;Surmeier et al. 1996;Tong et al. 1996). In particular, the wv mutation affects two regions of the CNS. In cerebellum, granule cell neurons die soon after birth as they fail to differentiate and migrate into the internal granule cell layer (Goldowitz, 1989;Hess, 1996). Large numbers of granule cells are lost (Rakic & Sidman, 1973a,b;Sidman, 1976) as well as lesser numbers of Purkinje cells (Smeyne & Goldowitz, 1990) producing the prominent ataxia characteristic of these animals. In addition, there is a severe depletion of tyrosine hydroxylase positive neurons in the midbrain (substantia nigra, pars compacta) (Schmidt et al. 1982; Roffler-Tarlov & Graybiel, 1986;Triarhou et al. 1986). These anatomical changes coexist with an altered distribution of GIRK1 and GIRK2 K¤ channel proteins throughout the brain . Putative GIRK2wv channels have been expressed in Xenopus oocytes and in CHO cells (Patil et al. 1995;Kofuji et al. 1996;Liao et al. 1996;Navarro et al. 1996;Silverman et al. 1996;Surmeier et al. 1996;Tong et al. 1996;Slesinger et al. 1996Slesinger et al. , 1997Lauritzen et al. 1997). GIRK1 subunits expressed by themselves do not form functional channels although it is believed that GIRK2 subunits can form functional homomeric channels (assuming there was no complementation by endogenous subunits in these experiments). Homomeric GIRK2wv channels expressed in oocytes produce a constitutively active non-selective inward current Navarro et al. 1996;Silverman et al. 1996;Slesinger et al. 1996;Tong et al. 1996) suggesting that GIRK2wv channels lose their selectivity for K¤ ions and their regulation by G-proteins. Native channels are believed to be comprised of both GIRK1 and GIRK2. Co-expression of wild-type GIRK1 and GIRK2 subunits produce large K¤-selective currents that are G-protein regulated (Slesinger et al. 1996). Co-expression of GIRK1 and GIRK2wv results in

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Evidence of elevated intracellular calcium levels in weaver homozygote mice

Harkins

Dlouhy

Ghetti

et al. 2000

The Journal of Physiology

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“…Interestingly, the vermis is the region most severely affected, whereas cell deficit is spared in cerebellar hemispheres (Herrup and Trenkner, 1987; Eisenman et al, 1998; Maricich et al, 1997; Martí et al, 2001). In the heterozygous weavers ( wv /+), neurodegeneration is less evident (Rezai and Yoon, 1972; Rakic and Sidman, 1973a,b; Herrup and Trenkner, 1987; Blatt and Eisenman, 1985; Won et al, 1997; Martí et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…In the heterozygous weavers (wv/+), neurodegeneration is less evident (Rezai and Yoon, 1972;http://dx.doi.org/10.1016/j.ijdevneu.2015.12.006 0736-5748/© 2016 Elsevier Ltd. All rights reserved. Sidman, 1973a,b;Herrup and Trenkner, 1987;Blatt and Eisenman, 1985;Won et al, 1997;Martí et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Generation and vulnerability of deep cerebellar nuclei neurons in the weaver condition along the anteroposterior and mediolateral axes

Martí

Santa-Cruz

Hervás

2015

Intl J of Devlp Neuroscience

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a b s t r a c tProduction and death of deep cerebellar nuclei (DCN) neurons were investigated in the weaver condition at appropriate anatomical levels throughout the mediolateral (medial, intermediate and lateral) and rostrocaudal (rostral, middle and caudal) axes of three DCN-cell groups: the fastigial, the interposed and the dentate nuclei. Current results have denoted that the deficit of DCN neurons is always more important in the homozygous weaver than in the heterozygous weaver mice. No loss of neurons was found in the dentate nucleus. In the mediolateral axis, an intranuclear gradient of depletion was observed in the mutant mice; in a given deep nucleus, neurodegeneration was more prominent in the medial pars than in lateral ones. In the rostrocaudal axis, on the other hand, when each deep nucleus was studied and compared as a whole, neuron loss was higher in the fastigial nucleus than in the interposed nucleus, which, in turn, was more important than in the dentate nucleus. These data suggest that, in the weaver condition, an internuclear gradient of neurodegeneration exists. Moreover, neurons located in rostral parts of a given nucleus appear to be more vulnerable than those settled in middle parts and these, in turn, are more than the caudal ones. These results seem to indicate the presence of an intranuclear gradient of depletion. Current autoradiographic results have revealed that, in the rostrocaudal axis, deep neurons are settled in the weaver cerebellum following three neurogenetic gradients. The first of these is internuclear; if each deep nucleus is analyzed and compared as a whole, the fastigial nucleus has more late-generated neurons than the interposed nucleus, and this, in turn, has more than the dentate nucleus. The second gradient is also internuclear; if the proportion of late-born neurons is compared throughout the rostral levels from each deep nucleus, it is observed that proportions increase from the fastigial to the dentate nucleus. A similar picture emerges when the middle and caudal regions are taken into account. The third gradient is intranuclear; in a given deep nucleus, the rostral region always presents more late-produced neurons than the middle region and these, in turn, more than in the caudal level.

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“…Η μετάλλαξη weaver προέκυψε με αυθόρμητο τρόπο το 1961 σε μια αποικία μυών του στελέχους C57BL/6J (Lane, 1964). Πρόκειται για μια υπολειπόμενη αυτοσωμική σημειακή μετάλλαξη με λάθος νόημα, που εντοπίζεται στο 16 ο χρωμόσωμα (Won et al, 1997).…”

Section: To γενετικο μοντελο Weaverunclassified

Αλληλεπιδράσεις των συστημάτων νευροδιαβίβασης ντοπαμίνης/αδενοσίνης στον εγκέφαλο των "weaver" μυών, γενετικού μοντέλου ντοπαμινεργικής απονεύρωσης

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In vitro evidence that the reduction in mesencepalic dopaminergic neurons in the weaver heterozygote is not due to a failure in target cell interaction

Cited by 9 publications

References 34 publications

Evidence of elevated intracellular calcium levels in weaver homozygote mice

Evidence of elevated intracellular calcium levels in weaver homozygote mice

Generation and vulnerability of deep cerebellar nuclei neurons in the weaver condition along the anteroposterior and mediolateral axes

Αλληλεπιδράσεις των συστημάτων νευροδιαβίβασης ντοπαμίνης/αδενοσίνης στον εγκέφαλο των "weaver" μυών, γενετικού μοντέλου ντοπαμινεργικής απονεύρωσης

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