Biology subjects

Jerabkova, K.

Publications and source records attributed to Jerabkova, K..

3 recordsLinked to original sources

bioRxiv2020

Deubiquitylase UCHL3 drives error correction at kinetochores and chromosome segregation independent of spindle assembly checkpoint

Equal segregation of chromosomes during mitosis ensures euploidy of daughter cells. Defects in this process may result in imbalance in chromosomal composition and cellular transformation. Two surveillance pathways, the spindle assembly checkpoint (SAC) and the error-correction (EC), exist at kinetochores that monitor microtubule attachment and faithful segregation of chromosomes at the metaphase to anaphase transition. However, the molecular understanding of the interplay between EC and SAC signaling remains limited. Here we describe a role of deubiquitylase UCHL3 in the regulation of EC pathway during mitosis. Downregulation or inhibition of UCHL3 leads to improper attachments of chromosomes to spindle microtubules and to chromosome alignment defects during metaphase. Frequent segregation errors during anaphase and consequently aneuploidy is also observed upon inactivation of UCHL3. Surprisingly, UCHL3 is not involved in SAC signaling as both recruitment of SAC proteins to kinetochores and timely anaphase onset are not perturbed in UCHL3-deficient cells. Mechanistically, UCHL3 interacts with and deubiquitylates the mitotic kinase Aurora B known to drive both SAC and EC signaling. UCHL3 promotes interaction of Aurora B with MCAK, important EC factor but does not regulate Aurora B binding to other interacting partners or subcellular localization of Aurora B. Our results thus suggest that UCHL3-mediated deubiquitylation functionally separates EC from SAC signaling during mitosis and is critical for maintenance of euploidy in human cells.

cell biology↗

bioRxiv2019

Intraflagellar transport complex B proteins regulate the Hippo effector Yap1 during cardiogenesis

Cilia and the intraflagellar transport (IFT) proteins involved in ciliogenesis are associated with congenital heart diseases (CHD). However, the molecular links between cilia, IFT proteins and cardiogenesis are yet to be established. Using a combination of biochemistry, genetics, and live imaging methods, we show that IFT complex B proteins (Ift88, Ift54 and Ift20) modulate the Hippo pathway effector YAP1 in zebrafish and mouse. We demonstrate that this interaction is key to restrict the formation of the proepicardium and the myocardium. In cellulo experiments suggest that IFT88 and IFT20 interact with YAP1 in the cytoplasm and functionally modulates its activity, identifying a molecular link between cilia related proteins and the Hippo pathway. Taken together, our results highlight a novel role for IFT complex B proteins during cardiogenesis and shed light on an unexpected mechanism of action for ciliary proteins in YAP1 regulation. These findings provide mechanistic insights into a non-canonical role for cilia related proteins during cardiogenesis.

developmental biology↗

bioRxiv2019

CRMP2 mediates Sema3F-dependent axon pruning and dendritic spine remodeling

Regulation of axon guidance and pruning of inappropriate synapses by class 3 semaphorins is key to development of neural circuits. Collapsin response mediator protein 2 (CRMP2) has been shown to regulate axon guidance by mediating Semaphorin 3A (Sema3A) signaling and its dysfunction has been linked to schizophrenia, however, nothing is known about its role in the synapse pruning. Here, using newly generated crmp2-/- mice we demonstrate that while CRMP2 has only a moderate effect on Sema3A-dependent axon guidance in vivo, it is essential for Sema3F-dependent axon pruning and dendritic spine remodeling. We first demonstrate that CRMP2 deficiency interferes with Sema3A signaling in compartmentalized neuron cultures and leads to a mild defect in axon guidance in peripheral nerves and corpus callosum. Strikingly, we show that crmp2-/- mice display more prominent defects in dendritic spine pruning and stereotyped axon pruning in hippocampus and visual cortex consistent with impaired Sema3F signaling and with autism spectrum disorder (ASD)-rather than schizophrenia-like phenotype. Indeed, we demonstrate that CRMP2 mediates Sema3F-induced axon retraction in primary neurons and that crmp2-/- mice display early postnatal behavioral changes linked to ASD. In conclusion, we demonstrate that CRMP2 is an essential mediator of Sema3F-dependent synapse pruning and its dysfunction in early postnatal stages shares histological and behavioral features of ASD.

neuroscience↗