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.
Highlights
Down syndrome is the most common chromosomal disorder affecting the nervous system in humans
Our findings implicate deficient calcineurin phosphatase signalling through overexpression of regulator of calcineurin 1 (RCAN1), an endogenous calcineurin inhibitor that is triplicated in Down syndrome, in contributing to aberrant development by interfering with receptor endocytosis and retrograde trophic signalling
To determine if the endocytosis defect with excess RCAN1 was specific to TrkA receptors, we examined the endocytosis of the Transferrin receptor (TfR), a prototypical constitutively internalized receptor45
Summary
Down syndrome is the most common chromosomal disorder affecting the nervous system in humans. 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. 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. Using transgenic mice trisomic for RCAN1 alone as well as genetically correcting RCAN1 levels in Down syndrome mice, we establish a causal link between increased RCAN1 dosage, impaired neurotrophin receptor trafficking and developmental abnormalities in the sympathetic nervous system in Down syndrome
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