FMRP regulates actin filament organization via the armadillo protein p0071

Abstract

Loss of fragile X mental retardation protein (FMRP) causes synaptic dysfunction and intellectual disability. FMRP is an RNAbinding protein that controls the translation or turnover of a subset of mRNAs. Identifying these target transcripts is an important step toward understanding the pathology of the disease. Here, we show that FMRP regulates actin organization and neurite outgrowth via the armadillo protein p0071. In mouse embryonic fibroblasts (MEFs) lacking FMRP (Fmr1−), the actin cytoskeleton was markedly reorganized with reduced stress fibers and F-actin/G-actin ratios compared to fibroblasts reexpressing the protein. FMRP interfered with the translation of the p0071 mRNA in a 3 ′ -UTR-dependent manner. Accordingly, FMRP-depleted cells revealed elevated levels of p0071 protein. The knockdown of p0071 in Fmr1− fibroblasts restored stress fibers and an elongated cell shape, thus rescuing the Fmr1− phenotype, whereas overexpression of p0071 in Fmr1+ cells mimicked the Fmr1− phenotype. Moreover, p0071 and FMRP regulated neurite outgrowth and branching in a diametrically opposed way in agreement with the negative regulation of p0071 by FMRP. These results identify p0071 as an important and novel FMRP target and strongly suggest that impaired actin cytoskeletal functions mediated by an excess of p0071 are key aspects underlying the fragile X syndrome.

Altered Redox Mitochondrial Biology in the Neurodegenerative Disorder Fragile X-Tremor/Ataxia Syndrome: Use of Antioxidants in Precision Medicine

“…This scenario seems to reconcile the defects at the level of cytoskeletal organization (1), mitochondrial network (20) and bioenergetics (20,21,24) described in cells from premutation carriers. Furthermore, considering that FMRP regulates the organization and dynamics of actin filaments (50,51), a key process in the morphogenesis of dendritic spines (50), and that actin seems to be involved in mitochondria function and dynamics (48,(52)(53)(54)(55)(56)(57), it could be hypothesized that altered cytoskeletal organization-as a Novartis, Roche/Genentech and Zynerba regarding treatment for fragile X syndrome. formation, inhibits Kreb's cycle, favors ketogenesis and lipogenesis from excess of acetylCoA that did not enter the Kreb's cycle.…”

p0071 interacts with E‐cadherin in the cytoplasm so as to promote the invasion and metastasis of non‐small cell lung cancer

“…The study about p0071 is very limited. As a target of fragile X mental retardation protein, it mediated actin cytoskeletal organization . p0071 regulated the perinuclear accumulation of Rab11 to mediate recycling .…”

Functional roles of p120ctn family of proteins in central neurons

“…p0071 overexpression in neurons promotes dendritic arborization in hippocampal neurons [63]. FMRP binds to the RNA encoding p0071 and loss of FMRP enhances the levels of p0071 through RNA-dependent mechanisms [63].…”

“…FMRP binds to the RNA encoding p0071 and loss of FMRP enhances the levels of p0071 through RNA-dependent mechanisms [63]. Loss of FMRP increases dendrite arborization in young hippocampal neurons [63]. Interestingly, concurrent knockdown of p0071 with FMRP knockdown restores the enhanced dendritic arbor observed with FMRP knockdown.…”

“…Loss of FMRP is associated with the fragile X syndrome. ARVCF is a target of FMRP and both proteins cooperate to regulate neurite outgrowth and branching [63]. …”