Jeremy Magescas

All Publications

• Inactivation of microtubule organizing center function of the centrosome is required for neuronal development and centriole elimination. bioRxiv : the preprint server for biology Ng, R., Magescas, J., Feldman, J. L. 2025

  Abstract

  Cell differentiation is marked by a dramatic reorganization of the microtubule cytoskeleton that enables diverse cell functions. Mitotic precursor cells arrange microtubules around centrosomes, which become activated as microtubule-organizing centers (MTOCs) through the recruitment of pericentriolar material (PCM) and microtubules to build the mitotic spindle. A hallmark of differentiation is the "inactivation" of centrosomal MTOC function through the loss of PCM and microtubules, yet the function of this inactivation is unknown. We developed a GFP-nanobody-based targeting tool to activate centrosomes in C. elegans differentiated cells. Ectopically activating centrosomes in sensory neurons perturbed microtubule polarity, dynein-mediated trafficking, and caused defects in cell morphology and dendrite pathfinding. Ectopic PCM perturbed ciliogenesis and also protected centrioles from elimination, another common feature of differentiation. By forcing centrosome activation in a fully differentiated cell in a developing organism, we show that centrosome inactivation is required for differentiation by directly contributing to cell form and function.

  View details for DOI 10.1101/2025.11.17.688953

  View details for PubMedID 41332590

  View details for PubMedCentralID PMC12667983

• MAP9/MAPH-9 supports axonemal microtubule doublets and modulates motor movement. Developmental cell Tran, M. V., Khuntsariya, D., Fetter, R. D., Ferguson, J. W., Wang, J. T., Long, A. F., Cote, L. E., Wellard, S. R., Vazquez-Martinez, N., Sallee, M. D., Genova, M., Magiera, M. M., Eskinazi, S., Lee, J. D., Peel, N., Janke, C., Stearns, T., Shen, K., Lansky, Z., Magescas, J., Feldman, J. L. 2023

  Abstract

  Microtubule doublets (MTDs) comprise an incomplete microtubule (B-tubule) attached to the side of a complete cylindrical microtubule. These compound microtubules are conserved in cilia across the tree of life; however, the mechanisms by which MTDs form and are maintained invivo remain poorly understood. Here, we identify microtubule-associated protein 9 (MAP9) as an MTD-associated protein. We demonstrate that C.elegans MAPH-9, a MAP9 homolog, is present during MTD assembly and localizes exclusively to MTDs, a preference that is in part mediated by tubulin polyglutamylation. We find that loss of MAPH-9 causes ultrastructural MTD defects, including shortened and/or squashed B-tubules with reduced numbers of protofilaments, dysregulated axonemal motor velocity, and perturbed cilia function. Because we find that the mammalian ortholog MAP9 localizes to axonemes in cultured mammalian cells and mouse tissues, we propose that MAP9/MAPH-9 plays a conserved role in regulating ciliary motors and supporting the structure of axonemal MTDs.

  View details for DOI 10.1016/j.devcel.2023.12.001

  View details for PubMedID 38159567

• Centriole-less pericentriolar material serves as a microtubule organizing center at the base of C.elegans sensory cilia. Current biology : CB Magescas, J., Eskinazi, S., Tran, M. V., Feldman, J. L. 2021

  Abstract

  During mitosis in animal cells, the centrosome acts as a microtubule organizing center (MTOC) to assemble the mitotic spindle. MTOC function at the centrosome is driven by proteins within the pericentriolar material (PCM), however the molecular complexity of the PCM makes it difficult to differentiate the proteins required for MTOC activity from other centrosomal functions. We used the natural spatial separation of PCM proteins during mitotic exit to identify a minimal module of proteins required for centrosomal MTOC function in C.elegans. Using tissue-specific degradation, we show that SPD-5, the functional homolog of CDK5RAP2, is essential for embryonic mitosis, while SPD-2/CEP192 and PCMD-1, which are essential in the one-cell embryo, are dispensable. Surprisingly, although the centriole is known to be degraded in the ciliated sensory neurons in C.elegans,1-3 we find evidence for "centriole-less PCM" at the base of cilia and use this structure as a minimal testbed to dissect centrosomal MTOC function. Super-resolution imaging revealed that this PCM inserts inside the lumen of the ciliary axoneme and directly nucleates the assembly of dendritic microtubules toward the cell body. Tissue-specific degradation in ciliated sensory neurons revealed a role for SPD-5 and the conserved microtubule nucleator gamma-TuRC, but not SPD-2 or PCMD-1, in MTOC function at centriole-less PCM. This MTOC function was in the absence of regulation by mitotic kinases, highlighting the intrinsic ability of these proteins to drive microtubule growth and organization and further supporting a model that SPD-5 is the primary driver of MTOC function at the PCM.

  View details for DOI 10.1016/j.cub.2021.03.022

  View details for PubMedID 33798428

• Inherited apicobasal polarity defines the key features of axon-dendrite polarity in a sensory neuron. Current biology : CB Lee, J., Magescas, J., Fetter, R. D., Feldman, J. L., Shen, K. 2021

  Abstract

  Neurons are highly polarized cells with morphologically and functionally distinct dendritic and axonal processes. The molecular mechanisms that establish axon-dendrite polarity in vivo are poorly understood. Here, we describe the initial polarization of posterior deirid (PDE), a ciliated mechanosensory neuron, during development in vivo through 4D live imaging with endogenously tagged proteins. PDE inherits and maintains apicobasal polarity from its epithelial precursor. Its apical domain is directly transformed into the ciliated dendritic tip through apical constriction, which is followed by axonal outgrowth from the opposite basal side of the cell. The apical Par complex and junctional proteins persistently localize at the developing dendritic domain throughout this transition. Consistent with their instructive role in axon-dendrite polarization, conditional depletion of the Par complex and junctional proteins results in robust defects in dendrite and axon formation. During apical constriction, a microtubule-organizing center (MTOC) containing the microtubule nucleator γ-tubulin ring complex (γ-TuRC) forms along the apical junction between PDE and its sister cell in a manner dependent on the Par complex and junctional proteins. This junctional MTOC patterns neuronal microtubule polarity and facilitate the dynein-dependent recruitment of the basal body for ciliogenesis. When non-ciliated neurons are genetically manipulated to obtain ciliated neuronal fate, inherited apicobasal polarity is required for generating ciliated dendritic tips. We propose that inherited apicobasal polarity, together with apical cell-cell interactions drive the morphological and cytoskeletal polarity in early neuronal differentiation.

  View details for DOI 10.1016/j.cub.2021.06.039

  View details for PubMedID 34270949

• A two-step mechanism for the inactivation of microtubule organizing center function at the centrosome. eLife Magescas, J., Zonka, J. C., Feldman, J. L. 2019; 8

  Abstract

  The centrosome acts as a microtubule organizing center (MTOC), orchestrating microtubules into the mitotic spindle through its pericentriolar material (PCM). This activity is biphasic, cycling through assembly and disassembly during the cell cycle. Although hyperactive centrosomal MTOC activity is a hallmark of some cancers, little is known about how the centrosome is inactivated as an MTOC. Analysis of endogenous PCM proteins in C. elegans revealed that the PCM is composed of partially overlapping territories organized into an inner and outer sphere that are removed from the centrosome at different rates and using different behaviors. We found that phosphatases oppose the addition of PCM by mitotic kinases, ultimately catalyzing the dissolution of inner sphere PCM proteins at the end of mitosis. The nature of the PCM appears to change such that the remaining aging PCM outer sphere is mechanically ruptured by cortical pulling forces, ultimately inactivating MTOC function at the centrosome.

  View details for DOI 10.7554/eLife.47867

  View details for PubMedID 31246171