title: Loss of neuronal potassium/chloride cotransporter 3 (KCC3) is responsible for the degenerative phenotype in a conditional mouse model of hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum.
abstract: Disruption of the potassium/chloride cotransporter 3 (KCC3), encoded by the SLC12A6 gene, causes hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and neurodegenerative disorder affecting both the peripheral nervous system and CNS. However, the precise role of KCC3 in the maintenance of ion homeostasis in the nervous system and the pathogenic mechanisms leading to HMSN/ACC remain unclear. We established two Slc12a6 Cre/LoxP transgenic mouse lines expressing C-terminal truncated KCC3 in either a neuron-specific or ubiquitous fashion. Our results suggest that neuronal KCC3 expression is crucial for axon volume control. We also demonstrate that the neuropathic features of HMSN/ACC are predominantly due to a neuronal KCC3 deficit, while the auditory impairment is due to loss of non-neuronal KCC3 expression. Furthermore, we demonstrate that KCC3 plays an essential role in inflammatory pain pathways. Finally, we observed hypoplasia of the corpus callosum in both mouse mutants and a marked decrease in axonal tracts serving the auditory cortex in only the general deletion mutant. Together, these results establish KCC3 as an important player in both central and peripheral nervous system maintenance.
authors.affiliation: Center of Excellence in Neuroscience of the Université de Montréal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, University of Montreal, Montréal, Québec H2L 4MI, Canada.
authors.forename: Masoud
authors.initials: M
authors.lastname: Shekarabi
authors.forename: Randal X
authors.initials: RX
authors.lastname: Moldrich
authors.forename: Sarah
authors.initials: S
authors.lastname: Rasheed
authors.forename: Adéle
authors.initials: A
authors.lastname: Salin-Cantegrel
authors.forename: Janet
authors.initials: J
authors.lastname: Laganière
authors.forename: Daniel
authors.initials: D
authors.lastname: Rochefort
authors.forename: Pascale
authors.initials: P
authors.lastname: Hince
authors.forename: Karine
authors.initials: K
authors.lastname: Huot
authors.forename: Rébecca
authors.initials: R
authors.lastname: Gaudet
authors.forename: Nyoman
authors.initials: N
authors.lastname: Kurniawan
authors.forename: Susana G
authors.initials: SG
authors.lastname: Sotocinal
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ritchie
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Dion
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Mogil
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Richards
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D061085:Agenesis of Corpus Callosum / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D027981:Symporters / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D000096922:K Cl- Cotransporters
chemical_list: D027981:Symporters; C492280:Slc12a6 protein, mouse; D000096922:K Cl- Cotransporters