Open AccessMECP2 mutations affect ciliogenesis: a novel perspective for Rett syndrome and related disorders
Author(s) -
Frasca Angelisa,
Spiombi Eleonora,
Palmieri Michela,
Albizzati Elena,
Valente Maria Maddalena,
Bergo Anna,
Leva Barbara,
KilstrupNielsen Charlotte,
Bianchi Federico,
Di Carlo Valerio,
Di Cunto Ferdinando,
Landsberger Nicoletta
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201910270
Subject(s) - ciliogenesis , rett syndrome , cilium , mecp2 , biology , centrosome , neuroscience , sonic hedgehog , microbiology and biotechnology , epigenetics , hedgehog signaling pathway , phenotype , mutation , genetics , signal transduction , cell , gene , cell cycle
Mutations in MECP 2 cause several neurological disorders of which Rett syndrome ( RTT ) represents the best‐defined condition. Although mainly working as a transcriptional repressor, Me CP 2 is a multifunctional protein revealing several activities, the involvement of which in RTT remains obscure. Besides being mainly localized in the nucleus, Me CP 2 associates with the centrosome, an organelle from which primary cilia originate. Primary cilia function as “sensory antennae” protruding from most cells, and a link between primary cilia and mental illness has recently been reported. We herein demonstrate that Me CP 2 deficiency affects ciliogenesis in cultured cells, including neurons and RTT fibroblasts, and in the mouse brain. Consequently, the cilium‐related Sonic Hedgehog pathway, which is essential for brain development and functioning, is impaired. Microtubule instability participates in these phenotypes that can be rescued by HDAC 6 inhibition together with the recovery of RTT ‐related neuronal defects. Our data indicate defects of primary cilium as a novel pathogenic mechanism that by contributing to the clinical features of RTT might impact on proper cerebellum/brain development and functioning, thus providing a novel therapeutic target.