Viral Infection or IFN-α Alters Mitotic Spindle Orientation by Modulating Pericentrin Levels.

Congenital microcephaly occurs in utero during Zika virus (ZIKV) infection. The single-gene disorder, Majewski osteodysplastic primordial dwarfism type II (MOPDII), also leads to microcephaly and is concomitant with a decrease in the centrosomal protein, pericentrin (PCNT). This protein is a known contributor of mitotic spindle misorientation and ultimately, microcephaly.

point mutations and familial intracranial aneurysms.

Objective: To identify novel genes involved in the etiology of intracranial aneurysms (IAs) or subarachnoid hemorrhages (SAHs) using whole-exome sequencing.

Methods: We performed whole-exome sequencing in 13 individuals from 3 families with an autosomal dominant IA/SAH inheritance pattern to look for candidate genes for disease. In addition, we sequenced exon 38 in a further 161 idiopathic patients with IA/SAH to find additional carriers of potential pathogenic variants.

New dimensions of asymmetric division in vertebrates.

Traditionally, we imagine that cell division gives rise to two identical daughter cells. Nevertheless, all cell divisions, to some degree, display asymmetry. Asymmetric cell division is defined as the generation of two daughter cells with different physical content and/or developmental potential.

The Centrosome, a Multitalented Renaissance Organelle.

The centrosome acts as a microtubule-organizing center (MTOC) from the G to G phases of the cell cycle; it can mature into a spindle pole during mitosis and/or transition into a cilium by elongating microtubules (MTs) from the basal body on cell differentiation or cell cycle arrest. New studies hint that the centrosome functions in more than MT organization. For instance, it has recently been shown that a specific substructure of the centrosome-the mother centriole appendages-are required for the recycling of endosomes back to the plasma membrane.

The Centrosome Undergoes Plk1-Independent Interphase Maturation during Inflammation and Mediates Cytokine Release.

Cytokine production is a necessary event in the immune response during inflammation and is associated with mortality during sepsis, autoimmune disorders, cancer, and diabetes. Stress-activated MAP kinase signaling cascades that mediate cytokine synthesis are well established. However, the downstream fate of cytokines before they are secreted remains elusive.

Human basal body basics.

In human cells, the basal body (BB) core comprises a ninefold microtubule-triplet cylindrical structure. Distal and subdistal appendages are located at the distal end of BB, where they play indispensable roles in cilium formation and function. Most cells that arrest in the G0 stage of the cell cycle initiate BB docking at the plasma membrane followed by BB-mediated growth of a solitary primary cilium, a structure required for sensing the extracellular environment and cell signaling.

The Mother Centriole Appendage Protein Cenexin Modulates Lumen Formation through Spindle Orientation.

Establishing apical-basal polarity is instrumental in the functional shaping of a solitary lumen within an acinus. By exploiting micropatterned slides, wound healing assays, and three-dimensional culture systems, we identified a mother centriole subdistal appendage protein, cenexin, as a critical player in symmetric lumen expansion through the control of microtubule organization. In this regard, cenexin was required for both centrosome positioning in interphase cells and proper spindle orientation during mitosis.

Multipolar mitosis and aneuploidy after chrysotile treatment: a consequence of abscission failure and cytokinesis regression.

Chrysotile, like other types of asbestos, has been associated with mesothelioma, lung cancer and asbestosis. However, the cellular abnormalities induced by these fibers involved in cancer development have not been elucidated yet. Previous works show that chrysotile fibers induce features of cancer cells, such as aneuploidy, multinucleation and multipolar mitosis.

Methods to analyze novel liaisons between endosomes and centrosomes.

For some time, it has been known that recycling endosomes (REs) are organized in a nebulous "pericentrosomal" region in interphase cells. However, the collective use of previously developed methods, including centrosome isolation, live cell imaging, and electron microscopy, suggested that there is much more going on between the centrosome and the RE than previously imagined. By exploiting these approaches, we uncovered novel roles of the centrosome in RE function and, conversely, novel roles for REs in centrosome function.

New frontiers: discovering cilia-independent functions of cilia proteins.

In most vertebrates, mitotic spindles and primary cilia arise from a common origin, the centrosome. In non-cycling cells, the centrosome is the template for primary cilia assembly and, thus, is crucial for their associated sensory and signaling functions. During mitosis, the duplicated centrosomes mature into spindle poles, which orchestrate mitotic spindle assembly, chromosome segregation, and orientation of the cell division axis.

Centrosome-intrinsic mechanisms modulate centrosome integrity during fever.

The centrosome is critical for cell division, ciliogenesis, membrane trafficking, and immunological synapse function. The immunological synapse is part of the immune response, which is often accompanied by fever/heat stress (HS). Here we provide evidence that HS causes deconstruction of all centrosome substructures primarily through degradation by centrosome-associated proteasomes.

The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes.

Background: Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly.

CPEB regulation of TAK1 synthesis mediates cytokine production and the inflammatory immune response.

The cytoplasmic-element-binding (CPEB) protein is a sequence-specific RNA-binding protein that regulates cytoplasmic polyadenylation-induced translation. In mouse embryo fibroblasts (MEFs) lacking CPEB, many mRNAs encoding proteins involved in inflammation are misregulated. Correlated with this aberrant translation in MEFs, a macrophage cell line depleted of CPEB and treated with lipopolysaccharide (LPS) to stimulate the inflammatory immune response expresses high levels of interleukin-6 (IL-6), which is due to prolonged nuclear retention of NF-κB.

A unique set of centrosome proteins requires pericentrin for spindle-pole localization and spindle orientation.

Majewski osteodysplastic primordial dwarfism type II (MOPDII) is caused by mutations in the centrosome gene pericentrin (PCNT) that lead to severe pre- and postnatal growth retardation. As in MOPDII patients, disruption of pericentrin (Pcnt) in mice caused a number of abnormalities including microcephaly, aberrant hemodynamics analyzed by in utero echocardiography, and cardiovascular anomalies; the latter being associated with mortality, as in the human condition. To identify the mechanisms underlying these defects, we tested for changes in cell and molecular function.

A new role for Rab GTPases during early mitotic stages.

A recent study revealed new roles for the Rab11 GTPase during mitosis. Rab11 is involved in recycling endosome localization to mitotic spindle poles via dynein-mediated transport. This process is in contrast to Golgi membranes, which disperse in mitosis and do not appear to directly contribute to mitotic functions.

Rab11 endosomes contribute to mitotic spindle organization and orientation.

During interphase, Rab11-GTPase-containing endosomes recycle endocytic cargo. However, little is known about Rab11 endosomes in mitosis. Here, we show that Rab11 localizes to the mitotic spindle and regulates dynein-dependent endosome localization at poles.

Resurrecting remnants: the lives of post-mitotic midbodies.

Around a century ago, the midbody (MB) was described as a structural assembly within the intercellular bridge during cytokinesis that served to connect the two future daughter cells. The MB has become the focus of intense investigation through the identification of a growing number of diverse cellular and molecular pathways that localize to the MB and contribute to its cytokinetic functions, ranging from selective vesicle trafficking and regulated microtubule (MT), actin, and endosomal sorting complex required for transport (ESCRT) filament assembly and disassembly to post-translational modification, such as ubiquitination. More recent studies have revealed new and unexpected functions of MBs in post-mitotic cells.

The centrosome regulates the Rab11- dependent recycling endosome pathway at appendages of the mother centriole.

The recycling endosome localizes to a pericentrosomal region via microtubule-dependent transport. We previously showed that Sec15, an effector of the recycling endosome component, Rab11-GTPase, interacts with the mother centriole appendage protein, centriolin, suggesting an interaction between endosomes and centrosomes. Here we show that the recycling endosome associates with the appendages of the mother (older) centriole.

Guidelines for the use and interpretation of assays for monitoring autophagy.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding.