Jacquemont, S. | Search bioRxiv

bioRxiv2019

Spatial control of nucleoporin assembly by Fragile X-related proteins

Nucleoporins (Nups) build highly organized Nuclear Pore Complexes (NPCs) at the nuclear envelope (NE). Several Nups assemble into a sieve-like hydrogel within the central channel of the NPCs to regulate nucleocytoplasmic exchange. In the cytoplasm, a large excess of soluble Nups has been reported, but how their assembly is restricted to the NE is currently unknown. Here we show that Fragile X-related protein 1 (FXR1) can interact with several Nups and facilitate their localization to the NE during interphase through a microtubule and dynein-dependent mechanism. Downregulation of FXR1 or closely related orthologs FXR2 and Fragile X mental retardation protein (FMRP) leads to the accumulation of cytoplasmic Nup protein condensates. Likewise, several models of Fragile X syndrome (FXS), characterized by a loss of FMRP, also accumulate cytoplasmic Nup aggregates. These aggregate-containing cells display aberrant nuclear morphology and a delay in G1 cell cycle progression. Our results reveal an unexpected role for the FXR protein family and dynein in the spatial regulation of nucleoporin assembly.\n\nHighlightsCytoplasmic nucleoporins are assembled by Fragile X-related (FXR) proteins and dynein\n\nFXR-Dynein pathway downregulation induces aberrant cytoplasmic aggregation of nucleoporins\n\nCellular models of Fragile X syndrome accumulate aberrant cytoplasmic nucleoporin aggregates.\n\nFXR-Dynein pathway regulates nuclear morphology and G1 cell cycle progression\n\neTOC BlurbNucleoporins (Nups) form Nuclear Pore Complexes (NPCs) at the nuclear envelope. Agote-Aran at al. show how cells inhibit aberrant assembly of Nups in the cytoplasm and identify Fragile X-related (FXR) proteins and dynein that facilitate localization of Nups to the nuclear envelope and control G1 cell cycle progression.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC=\"FIGDIR/small/767202v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (29K):\norg.highwire.dtl.DTLVardef@14a684borg.highwire.dtl.DTLVardef@53670org.highwire.dtl.DTLVardef@391907org.highwire.dtl.DTLVardef@9a290a_HPS_FORMAT_FIGEXP M_FIG Graphical abstract\n\nC_FIG

cell biology↗

bioRxiv2019

Leveraging biobank-scale rare and common variant analyses to identify ASPHD1 as the main driver of reproductive traits in the 16p11.2 locus

Whereas genome-wide association studies (GWAS) allowed identifying thousands of associations between variants and traits, their success rate in pinpointing causal genes has been disproportionately low. Here, we integrate biobank-scale phenotype data from carriers of a rare copy-number variant (CNV), Mendelian randomization and animal modeling to identify causative genes in a GWAS locus for age at menarche (AaM). We show that the dosage of the 16p11.2 BP4-BP5 interval is correlated positively with AaM in the UK and Estonian biobanks and 16p11.2 clinical cohorts, with a directionally consistent trend for pubertal onset in males. These correlations parallel an increase in reproductive tract disorders in both sexes. In support of these observations, 16p11.2 mouse models display perturbed pubertal onset and structurally altered reproductive organs that track with CNV dose. Further, we report a negative correlation between the 16p11.2 dosage and relative hypothalamic volume in both humans and mice, intimating a perturbation in the gonadotropin-releasing hormone (GnRH) axis. Two independent lines of evidence identified candidate causal genes for AaM; Mendelian randomization and agnostic dosage modulation of each 16p11.2 gene in zebrafish gnrh3:egfp models. ASPHD1, expressed predominantly in brain and pituitary gland, emerged as a major phenotype driver; and it is subject to modulation by KCTD13 to exacerbate GnRH neuron phenotype. Together, our data highlight the power of an interdisciplinary approach to elucidate disease etiologies underlying complex traits.

genomics↗