TY - JOUR
T1 - Clathrin heavy chain 22 contributes to the control of neuropeptide degradation and secretion during neuronal development
AU - Nahorski, Michael S.
AU - Borner, Georg H.H.
AU - Shaikh, Samiha S.
AU - Davies, Alexandra K.
AU - Al-Gazali, Lihadh
AU - Antrobus, Robin
AU - Woods, C. Geoffrey
N1 - Funding Information:
We thank Professor Margaret S Robinson, Dr Fiona Menzies, and Dr Lena Wartosch for their helpful discussions regarding Clathrin, lysosomal trafficking, and assisting us with some of the antibodies and reagents used in this study. We also thank the CIMR microscopy team of Mathew Gratian and Mark Bowen for their advice and assistance with microscopy. MSN and SS were funded by the MRC, RA by the Wellcome Trust, and CGW acknowledge support from the Cambridge NIHR BRC.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - The repertoire of cell types in the human nervous system arises through a highly orchestrated process, the complexity of which is still being discovered. Here, we present evidence that CHC22 has a non-redundant role in an early stage of neural precursor differentiation, providing a potential explanation of why CHC22 deficient patients are unable to feel touch or pain. We show the CHC22 effect on neural differentiation is independent of the more common clathrin heavy chain CHC17, and that CHC22-dependent differentiation is mediated through an autocrine/paracrine mechanism. Using quantitative proteomics, we define the composition of clathrin-coated vesicles in SH-SY5Y cells, and determine proteome changes induced by CHC22 depletion. In the absence of CHC22 a subset of dense core granule (DCG) neuropeptides accumulated, were processed into biologically active 'mature' forms, and secreted in sufficient quantity to trigger neural differentiation. When CHC22 is present, however, these DCG neuropeptides are directed to the lysosome and degraded, thus preventing differentiation. This suggests that the brief reduction seen in CHC22 expression in sensory neural precursors may license a step in neuron precursor neurodevelopment; and that this step is mediated through control of a novel neuropeptide processing pathway.
AB - The repertoire of cell types in the human nervous system arises through a highly orchestrated process, the complexity of which is still being discovered. Here, we present evidence that CHC22 has a non-redundant role in an early stage of neural precursor differentiation, providing a potential explanation of why CHC22 deficient patients are unable to feel touch or pain. We show the CHC22 effect on neural differentiation is independent of the more common clathrin heavy chain CHC17, and that CHC22-dependent differentiation is mediated through an autocrine/paracrine mechanism. Using quantitative proteomics, we define the composition of clathrin-coated vesicles in SH-SY5Y cells, and determine proteome changes induced by CHC22 depletion. In the absence of CHC22 a subset of dense core granule (DCG) neuropeptides accumulated, were processed into biologically active 'mature' forms, and secreted in sufficient quantity to trigger neural differentiation. When CHC22 is present, however, these DCG neuropeptides are directed to the lysosome and degraded, thus preventing differentiation. This suggests that the brief reduction seen in CHC22 expression in sensory neural precursors may license a step in neuron precursor neurodevelopment; and that this step is mediated through control of a novel neuropeptide processing pathway.
UR - http://www.scopus.com/inward/record.url?scp=85041686694&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041686694&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-19980-0
DO - 10.1038/s41598-018-19980-0
M3 - Article
C2 - 29402896
AN - SCOPUS:85041686694
SN - 2045-2322
VL - 8
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 2340
ER -