Relationship between the adrenal cortex and thymic involution in “lethargic” mutant mice

Dung, Houchi

doi:10.1002/aja.1001470209

Cited by 18 publications

(6 citation statements)

References 8 publications

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“…In contrast, mice exhibiting the neuropathy (Ͼ2 weeks old) showed a reduction in the CD4͞CD8 double-positive population (data not shown). Together, the data suggest that this reduction is secondary to the neuropathy including the corticosterone hypersecretion previously described in the mutant mice (33). This finding was confirmed by using RAG1 Ϫ/Ϫ bone marrow chimera mice to allow stem cells from both WT and ␤4 mutant to develop in similar physiological environment.…”

Section: Impairment Of Tcr-mediated Calcium͞nfat Pathway Activation Isupporting

confidence: 66%

Critical role for the β regulatory subunits of Cav channels in T lymphocyte function

Badou¹,

Jha²,

Matza³

et al. 2006

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

147

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Calcium ion is a universal signaling intermediate, which is known to control various biological processes. In excitable cells, voltagegated calcium channels (Cav) are the major route of calcium entry and regulate multiple functions such as contraction, neurotransmitter release, and gene transcription. Here we show that T lymphocytes, which are nonexcitable cells, express both regulatory ␤ and pore-forming Cav1 ␣1 subunits of Cav channels, and we provide genetic evidence for a critical role of the Cav ␤3 and Cav ␤4 regulatory subunits in T lymphocyte function. Cav ␤-deficient T lymphocytes fail to acquire normal functions, and they display impairment in the T cell receptor-mediated calcium response, nuclear factor of activated T cells activation, and cytokine production. In addition, unlike in excitable cells, our data suggest a minimal physiological role for depolarization in Cav channel opening in T cells. T cell receptor stimulation induces only a small depolarization of T cells, and artificial depolarization of T cells using KCl does not lead to calcium entry. These observations suggest that the Cav channels expressed by T cells have adopted novel regulation͞gating mechanisms.C alcium ion plays critical and specific roles in various T cell functions, including activation, differentiation, proliferation, and cytokine production (1, 2). In T lymphocytes, ligation of the T cell receptor (TCR) by antigen leads to the release of calcium from intracellular stores, triggering the calcium release-activated calcium current (3), and a potential candidate for calcium release-activated calcium current channel was recently reported (4-6). But the complexity of the calcium response in T cells suggests the expression of more than one plasma membrane calcium channel. Although it is established that, in excitable cells, Cav channels constitute the major route of calcium entry (7), the functional presence of the Cav1 channels in T lymphocytes has been suggested (8-13) but has remained controversial because of the lack of a reliable and specific loss-of-function approach.Cav ␤ subunits are cytoplasmic proteins that strongly regulate Cav channels through direct interaction with pore-forming ␣1 subunits (14-17). The ␤ subunits are also critical for assembly of the channel complex (18), correct plasma membrane targeting (19,20), and stimulation of channel activity (21). A number of potential ␣1-␤ combinations are likely to form a Cav channel complex (22), and, among these, the ␤4 and ␤3 subunits are key subunits that associate with Cav1 channels (23-25).A spontaneous mutation named lethargic, which arose in the mouse inbred strain BALB͞cGn in 1962, is recognizable in homozygous mice at 2 weeks of age by the onset of ataxia, seizures, and lethargic behavior (26,27). These mice also exhibit a generalized immunological disorder including defective cell-mediated immune responses (28). It has been reported, using a positional cloning approach, that this syndrome was the result of a mutation of the Cav ␤4 subunit gene (29). This mutatio...

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Section: Impairment Of Tcr-mediated Calcium͞nfat Pathway Activation Isupporting

confidence: 66%

Critical role for the β regulatory subunits of Cav channels in T lymphocyte function

Badou¹,

Jha²,

Matza³

et al. 2006

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

147

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“…In addition to the triad of neurological disorders, lethargic homozygotes show a slightly reduced body weight and transient defects in nonneuronal tissues including the immune system. 42 Neuropathological observations in lethargic mouse brain are limited compared with tottering, but also reveal a reduction in the size of the cerebellar molecular layer (D.L. Burgess, unpublished observations).…”

Section: The Tottering (Tg) Mousementioning

confidence: 99%

Voltage‐Dependent Calcium Channel Mutations in Neurological Disease

Burgess

Noebels

1999

Annals of the New York Academy of Sciences

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Calcium ion channel mutations disrupt channel function and create recognizable disease phenotypes in the nervous system. The broad array of underlying cellular alterations is commensurate with the expanding genetic diversity of the voltage-gated calcium ion channel complex and its critical role in regulating cell function. Currently, 16 calcium channel genes are known, and mutations in 7 of these are associated with distinct inherited neurological disorders. These mutations provide new insight into the structure and function of the channels, and link specific subunits to cellular disease processes, including altered excitability, synaptic signaling, and cell death. Studies of mutant channel behavior, subunit interactions, and the differentiation of neural networks demonstrate unique patterns of downstream rearrangement. Developmental analysis of molecular plasticity in these mutants is a critical step to define the intervening mechanisms that translate aberrant ion channel behavior into the diverse clinical phenotypes observed.

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“…Dung (1981) reported that the "lethargic" (Zh) mutation, on chromosome 2, causes a transient defect in cell mediated immune function accompanied by peripheral neuropathy. Adrenocortical hypersecretion may contribute to the mild immunodeficiency (Dung, 1976). Immunological studies of mice homozygous for the mutation "motor end plate disease" (medJ), on chromosome 15, revealed lymphoid hypoplasia and reduced T cell, B cell, and NK cell responses (Papiernik et al, 1982).…”

Section: Immune Defects In Neurological/neuromuscular Mutantsmentioning

confidence: 99%

Immunological mutants of the mouse

Shultz

1991

Am. J. Anat.

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Mutations at more than 30 loci in mice have been shown to cause deleterious effects on the immune system. Immunologic defects caused by certain of these mutations are determined at the level of hematopoietic progenitor cells or at the level of hematopoietic cell-stromal cell interactions. The immunological mutants described in this paper serve as experimental tools with which to increase our understanding of the development and regulation of the mammalian immune system.

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Relationship between the adrenal cortex and thymic involution in “lethargic” mutant mice

Cited by 18 publications

References 8 publications

Critical role for the β regulatory subunits of Cav channels in T lymphocyte function

Critical role for the β regulatory subunits of Cav channels in T lymphocyte function

Voltage‐Dependent Calcium Channel Mutations in Neurological Disease

Immunological mutants of the mouse

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