The dilute-lethal (dl) gene attacks a Ca2+ store in the dendritic spine of Purkinje cells in mice

doi:10.1016/0304-3940(96)12967-0

Neuroscience Letters

Volume 215, Issue 3, 13 September 1996, Pages 169-172

https://doi.org/10.1016/0304-3940(96)12967-0 Get rights and content

Abstract

The absence of smooth endoplasmic reticulum (SER) in the dendritic spine of Purkinje cells was found in dilute-lethal (d^l) mouse cerebella as detected by immunohistochemistry using anti-inositol 1,4,5-triphosphate receptor antibody and electron microscopy. Since SER in the spine has been suggested to play a crucial role for synaptic regulation as an intracellular Ca²⁺ store (for reviews, see [Miller, R.J., Prog. Neurobiol., 37 (1991) 255–285; Simpson, P.B., Challiss, R.A.J. and Nahorski, S.R., Trends Neurosci., 18 (1995) 299–306]), a neurological defect, characterized by clonic convulsions with opisthotonus and ataxia, in the dilute-lethal mouse with homozygous trait may be attributable to the absence of SER in the dendritic spine of Purkinje cells.

References (20)

K. Dekker-Ohno et al.
Endoplasmic reticulum is missing in dendritic spines of Purkinje cells of the ataxic mutant rat
Brain Res.
(1996)
L.J. Engle et al.
Cloning, analysis, and chromosomal localization of myoxin (MYH12), the human homologue to the mouse dilute gene
Genomics
(1994)
R.J. Miller
The control of neuronal Ca²⁺ homeostasis
Prog. Neurobiol.
(1991)
T. Noguchi et al.
Poor myelination in the central nervous system of ‘dilute-lethal mutant mice’ ( $d^{l} d^{l}$ )
Exp. Neurol.
(1983)
R. Shigemoto et al.
Antibodies inactivating mGluR1 metabotropic glutamate receptor block long-term depression in cultured Purkinje cells
Neuron
(1994)
P.B. Simpson et al.
Neruonal Ca²⁺ stores: activation and function
Trends Neurosci.
(1995)
Y. Takagishi et al.
Purkinje cell abnormalities and synaptogenesis in genetically jaundiced rats (Gunn rats)
Brain Res.
(1989)
A. Aiba et al.
Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice
Cell
(1994)
K. Dekker-Ohno et al.
An ataxic mutant rat with dilute coat color
Lab. Anim. Sci.
(1993)
E.M. Espreafico et al.
Primary structure and cellular localization of chicken brain myosin-V (p190), an unconventional myosin with calmodulin light chains
J. Cell Biol.
(1992)

There are more references available in the full text version of this article.

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As is typical for Myo5a mutations, the silvery-gray hair of the mutant rat shows pigment clumping due to accumulation of melanosomes in the hair shaft when compared with the normal hair shaft appearance (Fig. 2A and B) (Reissmann and Ludwig, 2013). Second, transmission electron microscopy confirmed the lack of smooth endoplasmic reticulum in Purkinje cell spines (Fig. 2C), as previously described in Myo5a mutant mice (Jones et al., 2000; Mercer et al., 1991; Takagishi et al., 1996) and rats (Dekker-Ohno et al., 1996). Finally, western blot analysis showed the complete lack of Myo5a protein, demonstrating that the splice mutation indeed leads to the loss of the Myo5a protein (Fig. 2D).
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^☆: This work was supported in part by the research grant from the Ministry of Education, Science, Sports and Culture of Japan (No. 07670708).

^∗: We wish to thank Dr. Katsuhiko Mikoshiba for the gift of anti-Ins P₃ antibody.

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Neuroscience Letters

Abstract

References (20)

Endoplasmic reticulum is missing in dendritic spines of Purkinje cells of the ataxic mutant rat

Brain Res.

Cloning, analysis, and chromosomal localization of myoxin (MYH12), the human homologue to the mouse dilute gene

Genomics

The control of neuronal Ca²⁺ homeostasis

Prog. Neurobiol.

Poor myelination in the central nervous system of ‘dilute-lethal mutant mice’ ( $d^{l} d^{l}$ )

Exp. Neurol.

Antibodies inactivating mGluR1 metabotropic glutamate receptor block long-term depression in cultured Purkinje cells

Neuron

Neruonal Ca²⁺ stores: activation and function

Trends Neurosci.

Purkinje cell abnormalities and synaptogenesis in genetically jaundiced rats (Gunn rats)

Brain Res.

Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice

Cell

An ataxic mutant rat with dilute coat color

Lab. Anim. Sci.

Primary structure and cellular localization of chicken brain myosin-V (p190), an unconventional myosin with calmodulin light chains

J. Cell Biol.

Cited by (140)

Genetic diseases predisposing to HLH

The actin motor MYO-5 effect in the intracellular organization of Neurospora crassa

Pleiotropic neuropathological and biochemical alterations associated with Myo5a mutation in a rat Model

Specialization of biosynthetic membrane trafficking for neuronal form and function

ER sheet-tubule balance is regulated by an array of actin filaments and microtubules

Genetic Diseases Predisposing to HLH

The dilute-lethal (dl) gene attacks a Ca2+ store in the dendritic spine of Purkinje cells in mice☆

Abstract

Brain Res.

Genomics

Prog. Neurobiol.

Exp. Neurol.

Neuron

Trends Neurosci.

Brain Res.

Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice

Cell

An ataxic mutant rat with dilute coat color

Lab. Anim. Sci.

Primary structure and cellular localization of chicken brain myosin-V (p190), an unconventional myosin with calmodulin light chains

J. Cell Biol.

The dilute-lethal (d^l) gene attacks a Ca²⁺ store in the dendritic spine of Purkinje cells in mice☆