Publications by authors named "Kassandra M Ori-McKenney"

15 Publications

  • Page 1 of 1

A Combinatorial MAP Code Dictates Polarized Microtubule Transport.

Dev Cell 2020 04 27;53(1):60-72.e4. Epub 2020 Feb 27.

Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA. Electronic address:

Many eukaryotic cells distribute their intracellular components asymmetrically through regulated active transport driven by molecular motors along microtubule tracks. While intrinsic and extrinsic regulation of motor activity exists, what governs the overall distribution of activated motor-cargo complexes within cells remains unclear. Here, we utilize in vitro reconstitution of purified motor proteins and non-enzymatic microtubule-associated proteins (MAPs) to demonstrate that MAPs exhibit distinct influences on the motility of the three main classes of transport motors: kinesin-1, kinesin-3, and cytoplasmic dynein. Further, we dissect how combinations of MAPs affect motors and unveil MAP9 as a positive modulator of kinesin-3 motility. From these data, we propose a general "MAP code" that has the capacity to strongly bias directed movement along microtubules and helps elucidate the intricate intracellular sorting observed in highly polarized cells such as neurons.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.devcel.2020.01.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181406PMC
April 2020

Microtubules gate tau condensation to spatially regulate microtubule functions.

Nat Cell Biol 2019 09 2;21(9):1078-1085. Epub 2019 Sep 2.

Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA, USA.

Tau is an abundant microtubule-associated protein in neurons. Tau aggregation into insoluble fibrils is a hallmark of Alzheimer's disease and other types of dementia, yet the physiological state of tau molecules within cells remains unclear. Using single-molecule imaging, we directly observe that the microtubule lattice regulates reversible tau self-association, leading to localized, dynamic condensation of tau molecules on the microtubule surface. Tau condensates form selectively permissible barriers, spatially regulating the activity of microtubule-severing enzymes and the movement of molecular motors through their boundaries. We propose that reversible self-association of tau molecules, gated by the microtubule lattice, is an important mechanism of the biological functions of tau, and that oligomerization of tau is a common property shared between the physiological and disease-associated forms of the molecule.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41556-019-0375-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748660PMC
September 2019

Dual control of Kinesin-1 recruitment to microtubules by Ensconsin in neuroblasts and oocytes.

Development 2019 04 17;146(8). Epub 2019 Apr 17.

Univ. Rennes, CNRS, IGDR (Institut de Génétique et Développement de Rennes) - UMR 6290, F-35000 Rennes, France

Ensconsin (also known as MAP7) controls spindle length, centrosome separation in brain neuroblasts (NBs) and asymmetric transport in oocytes. The control of spindle length by Ensconsin is Kinesin-1 independent but centrosome separation and oocyte transport require targeting of Kinesin-1 to microtubules by Ensconsin. However, the molecular mechanism used for this targeting remains unclear. Ensconsin contains a microtubule (MT)-binding domain (MBD) and a Kinesin-binding domain (KBD). Rescue experiments show that only full-length Ensconsin restores the spindle length phenotype. KBD expression rescues centrosome separation defects in NBs, but not the fast oocyte streaming and the localization of Staufen and Gurken. Interestingly, the KBD can stimulate Kinesin-1 targeting to MTs and We propose that a KBD and Kinesin-1 complex is a minimal activation module that increases Kinesin-1 affinity for MTs. Addition of the MBD present in full-length Ensconsin allows this process to occur directly on the MT and triggers higher Kinesin-1 targeting. This dual regulation by Ensconsin is essential for optimal Kinesin-1 targeting to MTs in oocytes, but not in NBs, illustrating the importance of adapting Kinesin-1 recruitment to different biological contexts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1242/dev.171579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503980PMC
April 2019

Psychedelics Promote Structural and Functional Neural Plasticity.

Cell Rep 2018 06;23(11):3170-3182

Department of Chemistry, University of California, Davis, Davis, CA 95616, USA; Center for Neuroscience, University of California, Davis, Davis, CA 95618, USA; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA. Electronic address:

Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2018.05.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082376PMC
June 2018

Competition between microtubule-associated proteins directs motor transport.

Nat Commun 2018 04 16;9(1):1487. Epub 2018 Apr 16.

Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA, 95616, USA.

Within cells, motor and non-motor microtubule-associated proteins (MAPs) simultaneously converge on the microtubule. How the binding activities of non-motor MAPs are coordinated and how they contribute to the balance and distribution of motor transport is unknown. Here, we examine the relationship between MAP7 and tau owing to their antagonistic roles in vivo. We find that MAP7 and tau compete for binding to microtubules, and determine a mechanism by which MAP7 displaces tau from the lattice. MAP7 promotes kinesin-based transport in vivo and strongly recruits kinesin-1 to the microtubule in vitro, providing evidence for direct enhancement of motor motility by a MAP. Both MAP7 and tau strongly inhibit kinesin-3 and have no effect on cytoplasmic dynein, demonstrating that MAPs differentially control distinct classes of motors. Overall, these results reveal a general principle for how MAP competition dictates access to the microtubule to determine the correct distribution and balance of motor activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-03909-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902456PMC
April 2018

Impact of diet-derived signaling molecules on human cognition: exploring the food-brain axis.

NPJ Sci Food 2017 30;1. Epub 2017 Oct 30.

9Department of Anatomy, Physiology & Cell Biology, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616 USA.

The processes that define mammalian physiology evolved millions of years ago in response to ancient signaling molecules, most of which were acquired by ingestion and digestion. In this way, evolution inextricably linked diet to all major physiological systems including the nervous system. The importance of diet in neurological development is well documented, although the mechanisms by which diet-derived signaling molecules (DSMs) affect cognition are poorly understood. Studies on the positive impact of nutritive and non-nutritive bioactive molecules on brain function are encouraging but lack the statistical power needed to demonstrate strong positive associations. Establishing associations between DSMs and cognitive functions like mood, memory and learning are made even more difficult by the lack of robust phenotypic markers that can be used to accurately and reproducibly measure the effects of DSMs. Lastly, it is now apparent that processes like neurogenesis and neuroplasticity are embedded within layers of interlocked signaling pathways and gene regulatory networks. Within these interdependent pathways and networks, the various transducers of DSMs are used combinatorially to produce those emergent adaptive gene expression responses needed for stimulus-induced neurogenesis and neuroplasticity. Taken together, it appears that cognition is encoded genomically and modified by epigenetics and epitranscriptomics to produce complex transcriptional programs that are exquisitely sensitive to signaling molecules from the environment. Models for how DSMs mediate the interplay between the environment and various neuronal processes are discussed in the context of the food-brain axis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41538-017-0002-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548416PMC
October 2017

ReMAPping the microtubule landscape: How phosphorylation dictates the activities of microtubule-associated proteins.

Dev Dyn 2018 01 27;247(1):138-155. Epub 2017 Oct 27.

Department of Molecular and Cellular Biology, University of California, Davis, CA.

Classical microtubule-associated proteins (MAPs) were originally identified based on their co-purification with microtubules assembled from mammalian brain lysate. They have since been found to perform a range of functions involved in regulating the dynamics of the microtubule cytoskeleton. Most of these MAPs play integral roles in microtubule organization during neuronal development, microtubule remodeling during neuronal activity, and microtubule stabilization during neuronal maintenance. As a result, mutations in MAPs contribute to neurodevelopmental disorders, psychiatric conditions, and neurodegenerative diseases. MAPs are post-translationally regulated by phosphorylation depending on developmental time point and cellular context. Phosphorylation can affect the microtubule affinity, cellular localization, or overall function of a particular MAP and can thus have profound implications for neuronal health. Here we review MAP1, MAP2, MAP4, MAP6, MAP7, MAP9, tau, and DCX, and how each is regulated by phosphorylation in neuronal physiology and disease. Developmental Dynamics 247:138-155, 2018. © 2017 Wiley Periodicals, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/dvdy.24599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739964PMC
January 2018

Phosphorylation of β-Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis.

Neuron 2016 05 21;90(3):551-63. Epub 2016 Apr 21.

Department of Physiology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address:

Dendritic arborization patterns are consistent anatomical correlates of genetic disorders such as Down syndrome (DS) and autism spectrum disorders (ASDs). In a screen for abnormal dendrite development, we identified Minibrain (MNB)/DYRK1a, a kinase implicated in DS and ASDs, as a regulator of the microtubule cytoskeleton. We show that MNB is necessary to establish the length and cytoskeletal composition of terminal dendrites by controlling microtubule growth. Altering MNB levels disrupts dendrite morphology and perturbs neuronal electrophysiological activity, resulting in larval mechanosensation defects. Using in vivo and in vitro approaches, we uncover a molecular pathway whereby direct phosphorylation of β-tubulin by MNB inhibits tubulin polymerization, a function that is conserved for mammalian DYRK1a. Our results demonstrate that phosphoregulation of microtubule dynamics by MNB/DYRK1a is critical for dendritic patterning and neuronal function, revealing a previously unidentified mode of posttranslational microtubule regulation in neurons and uncovering a conserved pathway for a DS- and ASD-associated kinase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuron.2016.03.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860041PMC
May 2016

Golgi outposts shape dendrite morphology by functioning as sites of acentrosomal microtubule nucleation in neurons.

Neuron 2012 Dec;76(5):921-30

Howard Hughes Medical Institute, Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA.

Microtubule nucleation is essential for proper establishment and maintenance of axons and dendrites. Centrosomes, the primary site of nucleation in most cells, lose their function as microtubule organizing centers during neuronal development. How neurons generate acentrosomal microtubules remains unclear. Drosophila dendritic arborization (da) neurons lack centrosomes and therefore provide a model system to study acentrosomal microtubule nucleation. Here, we investigate the origin of microtubules within the elaborate dendritic arbor of class IV da neurons. Using a combination of in vivo and in vitro techniques, we find that Golgi outposts can directly nucleate microtubules throughout the arbor. This acentrosomal nucleation requires gamma-tubulin and CP309, the Drosophila homolog of AKAP450, and contributes to the complex microtubule organization within the arbor and dendrite branch growth and stability. Together, these results identify a direct mechanism for acentrosomal microtubule nucleation within neurons and reveal a function for Golgi outposts in this process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuron.2012.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523279PMC
December 2012

Regeneration of Drosophila sensory neuron axons and dendrites is regulated by the Akt pathway involving Pten and microRNA bantam.

Genes Dev 2012 Jul 3;26(14):1612-25. Epub 2012 Jul 3.

Howard Hughes Medical Institute, Department of Physiology, Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94158, USA.

Both cell-intrinsic and extrinsic pathways govern axon regeneration, but only a limited number of factors have been identified and it is not clear to what extent axon regeneration is evolutionarily conserved. Whether dendrites also regenerate is unknown. Here we report that, like the axons of mammalian sensory neurons, the axons of certain Drosophila dendritic arborization (da) neurons are capable of substantial regeneration in the periphery but not in the CNS, and activating the Akt pathway enhances axon regeneration in the CNS. Moreover, those da neurons capable of axon regeneration also display dendrite regeneration, which is cell type-specific, developmentally regulated, and associated with microtubule polarity reversal. Dendrite regeneration is restrained via inhibition of the Akt pathway in da neurons by the epithelial cell-derived microRNA bantam but is facilitated by cell-autonomous activation of the Akt pathway. Our study begins to reveal mechanisms for dendrite regeneration, which depends on both extrinsic and intrinsic factors, including the PTEN-Akt pathway that is also important for axon regeneration. We thus established an important new model system--the fly da neuron regeneration model that resembles the mammalian injury model--with which to study and gain novel insights into the regeneration machinery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gad.193243.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404388PMC
July 2012

Multiple modes of cytoplasmic dynein regulation.

Nat Cell Biol 2012 Feb 29;14(3):224-30. Epub 2012 Feb 29.

Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.

In performing its multiple cellular functions, the cytoplasmic dynein motor is subject to complex regulation involving allosteric mechanisms within the dynein complex, as well as numerous extramolecular interactions controlling subcellular targeting and motor activity. Recent work has distinguished high- and low-load regulatory modes for cytoplasmic dynein, which, combined with a diversity of targeting mechanisms, accounts for a very broad range of functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncb2420DOI Listing
February 2012

High-resolution imaging reveals indirect coordination of opposite motors and a role for LIS1 in high-load axonal transport.

J Cell Biol 2011 Oct;195(2):193-201

Department of Pathology and Cell Biology, Columbia University, New York, NY 10027, USA.

The specific physiological roles of dynein regulatory factors remain poorly understood as a result of their functional complexity and the interdependence of dynein and kinesin motor activities. We used a novel approach to overcome these challenges, combining acute in vivo inhibition with automated high temporal and spatial resolution particle tracking. Acute dynein inhibition in nonneuronal cells caused an immediate dispersal of diverse forms of cargo, resulting from a sharp decrease in microtubule minus-end run length followed by a gradual decrease in plus-end runs. Acute LIS1 inhibition or LIS1 RNA interference had little effect on lysosomes/late endosomes but severely inhibited axonal transport of large, but not small, vesicular structures. Our acute inhibition results argue against direct mechanical activation of opposite-directed motors and offer a novel approach of potential broad utility in the study of motor protein function in vivo. Our data also reveal a specific but cell type-restricted role for LIS1 in large vesicular transport and provide the first quantitative support for a general role for LIS1 in high-load dynein functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1083/jcb.201104076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198168PMC
October 2011

Neuronal migration defects in the Loa dynein mutant mouse.

Neural Dev 2011 May 25;6:26. Epub 2011 May 25.

Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.

Background: Cytoplasmic dynein and its regulatory proteins have been implicated in neuronal and non-neuronal cell migration. A genetic model for analyzing the role of cytoplasmic dynein specifically in these processes has, however, been lacking. The Loa (Legs at odd angles) mouse with a mutation in the dynein heavy chain has been the focus of an increasing number of studies for its role in neuron degeneration. Despite the location of this mutation in the tail domain of the dynein heavy chain, we previously found a striking effect on coordination between the two dynein motor domains, resulting in a defect in dynein run length in vitro and in vivo.

Results: We have now tested for effects of the Loa mutation on neuronal migration in the developing neocortex. Loa homozygotes showed clear defects in neocortical lamination and neuronal migration resulting from a reduction in the rate of radial migration of bipolar neurons.

Conclusions: These results present a new genetic model for understanding the dynein pathway and its functions during neuronal migration. They also provide the first evidence for a link between dynein processivity and somal movement, which is essential for proper development of the brain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1749-8104-6-26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3127822PMC
May 2011

A cytoplasmic dynein tail mutation impairs motor processivity.

Nat Cell Biol 2010 Dec 21;12(12):1228-34. Epub 2010 Nov 21.

Department of Pathology and Cell Biology, Columbia University. New York, NY 10032, USA.

Mutations in the tail of the cytoplasmic dynein molecule have been reported to cause neurodegenerative disease in mice. The mutant mouse strain Legs at odd angles (Loa) has impaired retrograde axonal transport, but the molecular deficiencies in the mutant dynein molecule, and how they contribute to neurodegeneration, are unknown. To address these questions, we purified dynein from wild-type mice and the Legs at odd angles mutant mice. Using biochemical, single-molecule, and live-cell-imaging techniques, we find a marked inhibition of motor run-length in vitro and in vivo, and significantly altered motor domain coordination in the dynein from mutant mice. These results suggest a potential role for the dynein tail in motor function, and provide direct evidence for a link between single-motor processivity and disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncb2127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385513PMC
December 2010

Development and application of in vivo molecular traps reveals that dynein light chain occupancy differentially affects dynein-mediated processes.

Proc Natl Acad Sci U S A 2010 Feb 4;107(8):3493-8. Epub 2010 Feb 4.

Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.

The ability to rapidly and specifically regulate protein activity combined with in vivo functional assays and/or imaging can provide unique insight into underlying molecular processes. Here we describe the application of chemically induced dimerization of FKBP to create nearly instantaneous high-affinity bivalent ligands capable of sequestering cellular targets from their endogenous partners. We demonstrate the specificity and efficacy of these inducible, dimeric "traps" for the dynein light chains LC8 (Dynll1) and TcTex1 (Dynlt1). Both light chains can simultaneously bind at adjacent sites of dynein intermediate chain at the base of the dynein motor complex, yet their specific function with respect to the dynein motor or other interacting proteins has been difficult to dissect. Using these traps in cultured mammalian cells, we observed that induction of dimerization of either the LC8 or TcTex1 trap rapidly disrupted early endosomal and lysosomal organization. Dimerization of either trap also disrupted Golgi organization, but at a substantially slower rate. Using either trap, the time course for disruption of each organelle was similar, suggesting a common regulatory mechanism. However, despite the essential role of dynein in cell division, neither trap had a discernable effect on mitotic progression. Taken together, these studies suggest that LC occupancy of the dynein motor complex directly affects some, but not all, dynein-mediated processes. Although the described traps offer a method for rapid inhibition of dynein function, the design principle can be extended to other molecular complexes for in vivo studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.0908959107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840451PMC
February 2010