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PMID:25149514

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Citation

Wessels, D, Lusche, DF, Scherer, A, Kuhl, S, Myre, MA and Soll, DR (2014) Huntingtin regulates Ca(2+) chemotaxis and K(+)-facilitated cAMP chemotaxis, in conjunction with the monovalent cation/H(+) exchanger Nhe1, in a model developmental system: insights into its possible role in Huntington׳s disease. Dev. Biol. 394:24-38

Abstract

Huntington׳s disease is a neurodegenerative disorder, attributable to an expanded trinucleotide repeat in the coding region of the human HTT gene, which encodes the protein huntingtin. These mutations lead to huntingtin fragment inclusions in the striatum of the brain. However, the exact function of normal huntingtin and the defect causing the disease remain obscure. Because there are indications that huntingtin plays a role in Ca(2+) homeostasis, we studied the deletion mutant of the HTT ortholog in the model developmental system Dictyostelium discoideum, in which Ca(2+) plays a role in receptor-regulated behavior related to the aggregation process that leads to multicellular morphogenesis. The D. discoideum htt(-)-mutant failed to undergo both K(+)-facilitated chemotaxis in spatial gradients of the major chemoattractant cAMP, and chemotaxis up a spatial gradient of Ca(2+), but behaved normally in Ca(2+)-facilitated cAMP chemotaxis and Ca(2+)-dependent flow-directed motility. This was the same phenotypic profile of the null mutant of Nhel, a monovalent cation/H(+)exchanger. The htt(-)-mutant also failed to orient correctly during natural aggregation, as was the case for the Nhel mutant. Moreover, in a K(+)-based buffer the normal localization of actin was similarly defective in both htt(-) and nhe1(-) cells in a K(+)-based buffer, and the normal localization of Nhe1 was disrupted in the htt(-) mutant. These observations demonstrate that Htt and Nhel play roles in the same specific cation-facilitated behaviors and that Nhel localization is directly or indirectly regulated by Htt. Similar cation-dependent behaviors and a similar relationship between Htt and Nhe1 have not been reported for mammalian neurons and deserves investigation, especially as it may relate to Huntington׳s disease.

Links

PubMed Online version:10.1016/j.ydbio.2014.08.009

Keywords

Actins/metabolism; Calcium/metabolism; Cation Transport Proteins/genetics; Cell Aggregation/genetics; Chemotaxis/genetics; Cyclic AMP/metabolism; Dictyostelium/genetics; Dictyostelium/physiology; Gene Deletion; Huntington Disease; Potassium/metabolism; Protozoan Proteins/genetics; Sodium-Hydrogen Antiporter/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DICDI:NHE1

acts_upstream_of_or_within

GO:0006935: chemotaxis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DICDI:NHE1

is_active_in

GO:0031252: cell leading edge

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DICDI:HD

acts_upstream_of_or_within

GO:0051592: response to calcium ion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DICDI:HD

acts_upstream_of_or_within

GO:0035864: response to potassium ion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DICDI:HD

acts_upstream_of_or_within

GO:1902463: protein localization to cell leading edge

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:Q552S0)

Seeded From UniProt

complete

DICDI:HD

acts_upstream_of_or_within

GO:0006935: chemotaxis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DICDI:HD

acts_upstream_of_or_within

GO:1902463: protein localization to cell leading edge

ECO:0000315: mutant phenotype evidence used in manual assertion

P

has_input:(UniProtKB:Q552S0)

Seeded From UniProt

complete

DICDI:HD

acts_upstream_of_or_within

GO:0051592: response to calcium ion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

happens_during:(GO:0006935)

Seeded From UniProt

complete

DICDI:HD

acts_upstream_of_or_within

GO:0035864: response to potassium ion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

happens_during:(GO:0006935)

Seeded From UniProt

complete

Notes

See also

References

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