title: RCAN1 links impaired neurotrophin trafficking to aberrant development of the sympathetic nervous system in Down syndrome.
abstract: Down syndrome is the most common chromosomal disorder affecting the nervous system in humans. To date, investigations of neural anomalies in Down syndrome have focused on the central nervous system, although dysfunction of the peripheral nervous system is a common manifestation. The molecular and cellular bases underlying peripheral abnormalities have remained undefined. Here, we report the developmental loss of sympathetic innervation in human Down syndrome organs and in a mouse model. We show that excess regulator of calcineurin 1 (RCAN1), an endogenous inhibitor of the calcineurin phosphatase that is triplicated in Down syndrome, impairs neurotrophic support of sympathetic neurons by inhibiting endocytosis of the nerve growth factor (NGF) receptor, TrkA. Genetically correcting RCAN1 levels in Down syndrome mice markedly improves NGF-dependent receptor trafficking, neuronal survival and innervation. These results uncover a critical link between calcineurin signalling, impaired neurotrophin trafficking and neurodevelopmental deficits in the peripheral nervous system in Down syndrome.
authors.affiliation: Department of Biology, Johns Hopkins University, 3400N. Charles Street, 224 Mudd Hall, Baltimore, Maryland 21218, USA.
authors.forename: Ami
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Biology, Johns Hopkins University, 3400N. Charles Street, 224 Mudd Hall, Baltimore, Maryland 21218, USA.
authors.forename: Naoya
authors.identifier: http://orcid.org/0000-0001-7667-5264
authors.initials: N
authors.lastname: Yamashita
authors.affiliation: Department of Biology, Johns Hopkins University, 3400N. Charles Street, 224 Mudd Hall, Baltimore, Maryland 21218, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Ascaño
authors.affiliation: Department of Biology, Johns Hopkins University, 3400N. Charles Street, 224 Mudd Hall, Baltimore, Maryland 21218, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bodmer
authors.affiliation: Department of Biology, Johns Hopkins University, 3400N. Charles Street, 224 Mudd Hall, Baltimore, Maryland 21218, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Boehm
authors.affiliation: Department of Biology, Johns Hopkins University, 3400N. Charles Street, 224 Mudd Hall, Baltimore, Maryland 21218, USA.
authors.forename: Chantal
authors.initials: C
authors.lastname: Bodkin-Clarke
authors.affiliation: Department of Biology, Johns Hopkins University, 3400N. Charles Street, 224 Mudd Hall, Baltimore, Maryland 21218, USA.
authors.forename: Yun Kyoung
authors.initials: YK
authors.lastname: Ryu
authors.affiliation: Department of Biology, Johns Hopkins University, 3400N. Charles Street, 224 Mudd Hall, Baltimore, Maryland 21218, USA.
authors.forename: Rejji
authors.initials: R
authors.lastname: Kuruvilla
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D004314:Down Syndrome / Q000378:metabolism*; D034284:Dynamin I / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology*; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000254:growth & development* / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; C511512:DSCR1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D009414:Nerve Growth Factors; D014446:Tyrosine 3-Monooxygenase; D020917:Receptor, trkA; D034284:Dynamin I