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https://www.readbyqxmd.com/read/27799303/different-doublecortin-dcx-patient-alleles-show-distinct-phenotypes-in-cultured-neurons-evidence-for-divergent-loss-of-function-and-off-pathway-cellular-mechanisms
#1
Chan Choo Yap, Laura Digilio, Lloyd McMahon, Matylda Roszkowska, Christopher J Bott, Kamil Kruczek, Bettina Winckler
DCX (doublecortin on the X-chromosome) is a neuronal microtubule-binding protein with a multitude of roles in neurodevelopment. In humans, DCX is a major genetic locus for X-linked lissencephaly. The best-studied defects are in neuronal migration during corticogenesis and in the hippocampus, as well as axon and dendrite growth defects. Much effort has been directed at understanding the molecular and cellular bases of DCX-linked lissencephaly. The focus has been in particular on defects in microtubule assembly and bundling, using knock-out mice and expression of WT and mutant DCX in non-neuronal cells...
October 31, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27528089/editorial-overview-cellular-neuroscience
#2
EDITORIAL
Mikael Simons, Bettina Winckler
No abstract text is available yet for this article.
August 2016: Current Opinion in Neurobiology
https://www.readbyqxmd.com/read/27503831/the-neurotrophin-receptor-signaling-endosome-where-trafficking-meets-signaling
#3
Kelly Barford, Christopher Deppmann, Bettina Winckler
Neurons are the largest cells in the body and form subcellular compartments such as axons and dendrites. During both development and adulthood building blocks must be continually trafficked long distances to maintain the different regions of the neuron. Beyond building blocks, signaling complexes are also transported, allowing for example, axons to communicate with the soma. The critical roles of signaling via ligand-receptor complexes is perhaps best illustrated in the context of development, where they are known to regulate polarization, survival, axon outgrowth, dendrite development, and synapse formation...
August 9, 2016: Developmental Neurobiology
https://www.readbyqxmd.com/read/26794525/studying-endosomes-in-cultured-neurons-by-live-cell-imaging
#4
Zofia M Lasiecka, Bettina Winckler
Endosomes play critical roles on regulating surface receptor levels as well as signaling cascades in all cell types, including neurons. Endocytosis and endosomal trafficking is routinely studied after fixation, but live imaging is increasingly being used to capture the dynamic nature of endosomes and is allowing increasingly sophisticated glimpses into trafficking processes in live neurons. In this chapter, we describe the basics of neuronal primary cultures, methods for expressing fluorescent proteins, and live imaging of cargos and endosomal regulators...
2016: Methods in Cell Biology
https://www.readbyqxmd.com/read/26465886/ctip2-satb2-prox1-and-gad65-expressing-neurons-in-rat-cultures-preponderance-of-single-and-double-positive-cells-and-cell-type-specific-expression-of-neuron-specific-gene-family-members-nsg-1-neep21-and-nsg-2-p19
#5
Laura Digilio, Chan Choo Yap, Bettina Winckler
The brain consists of many distinct neuronal cell types, but which cell types are present in widely used primary cultures of embryonic rodent brain is often not known. We characterized how abundantly four cell type markers (Ctip2, Satb2, Prox1, GAD65) were represented in cultured rat neurons, how easily neurons expressing different markers can be transfected with commonly used plasmids, and whether neuronal-enriched endosomal proteins Nsg-1 (NEEP21) and Nsg-2 (P19) are ubiquitously expressed in all types of cultured neurons...
2015: PloS One
https://www.readbyqxmd.com/read/25904845/adapting-for-endocytosis-roles-for-endocytic-sorting-adaptors-in-directing-neural-development
#6
REVIEW
Chan Choo Yap, Bettina Winckler
Proper cortical development depends on the orchestrated actions of a multitude of guidance receptors and adhesion molecules and their downstream signaling. The levels of these receptors on the surface and their precise locations can greatly affect guidance outcomes. Trafficking of receptors to a particular surface locale and removal by endocytosis thus feed crucially into the final guidance outcomes. In addition, endocytosis of receptors can affect downstream signaling (both quantitatively and qualitatively) and regulated endocytosis of guidance receptors is thus an important component of ensuring proper neural development...
2015: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/25355216/maturational-conversion-of-dendritic-early-endosomes-and-their-roles-in-l1-mediated-axon-growth
#7
Zofia M Lasiecka, Chan Choo Yap, Joshua Katz, Bettina Winckler
The function of endosomes is intricately linked to cellular function in all cell types, including neurons. Intriguingly, neurons express cell type-specific proteins that localize to endosomes, but little is known about how these neuronal proteins interface with canonical endosomes and ubiquitously expressed endosomal components, such as EEA1 (Early Endosomal Antigen 1). NEEP21 (Neuronal Early Endosomal Protein 21 kDa) localizes to somatodendritic endosomes, and downregulation of NEEP21 perturbs the correct trafficking of multiple receptors, including glutamate receptors (GluA2) during LTP and amyloidogenic processing of βAPP...
October 29, 2014: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/24299204/a-potassium-leak-channel-silences-hyperactive-neurons-and-ameliorates-status-epilepticus
#8
Deblina Dey, Veit-Simon Eckle, Iuliia Vitko, Kyle A Sullivan, Zofia M Lasiecka, Bettina Winckler, Ruth L Stornetta, John M Williamson, Jaideep Kapur, Edward Perez-Reyes
OBJECTIVE: To develop a constitutively active K(+) leak channel using TREK-1 (TWIK-related potassium channel 1; TREK-M) that is resistant to compensatory down-regulation by second messenger cascades, and to validate the ability of TREK-M to silence hyperactive neurons using cultured hippocampal neurons. To test if adenoassociated viral (AAV) delivery of TREK-M could reduce the duration of status epilepticus and reduce neuronal death induced by lithium-pilocarpine administration. METHODS: Molecular cloning techniques were used to engineer novel vectors to deliver TREK-M via plasmids, lentivirus, and AAV using a cytomegalovirus (CMV)-enhanced GABRA4 promoter...
February 2014: Epilepsia
https://www.readbyqxmd.com/read/24277868/mechanisms-by-which-a-cacna1h-mutation-in-epilepsy-patients-increases-seizure-susceptibility
#9
Veit-Simon Eckle, Aleksandr Shcheglovitov, Iuliia Vitko, Deblina Dey, Chan Choo Yap, Bettina Winckler, Edward Perez-Reyes
T-type calcium channels play essential roles in regulating neuronal excitability and network oscillations in the brain. Mutations in the gene encoding Cav3.2 T-type Ca(2+) channels, CACNA1H, have been found in association with various forms of idiopathic generalized epilepsy. We and others have found that these mutations may influence neuronal excitability either by altering the biophysical properties of the channels or by increasing their surface expression. The goals of the present study were to investigate the excitability of neurons expressing Cav3...
February 15, 2014: Journal of Physiology
https://www.readbyqxmd.com/read/24094097/acid-indigestion-in-the-endosome-linking-signaling-dysregulation-to-neurodevelopmental-disorders
#10
COMMENT
Chan Choo Yap, Bettina Winckler
The sodium-proton exchanger NHE6 contributes to proper endosomal acidification. NHE6 mutations are also linked to autism-related disorders. In this issue of Neuron, using NHE6-knockout mice, Ouyang et al. (2013) uncover how dysregulation of endosomal pH leads to disturbances in BDNF signaling and neuronal morphogenesis defects.
October 2, 2013: Neuron
https://www.readbyqxmd.com/read/23303949/doublecortin-dcx-family-proteins-regulate-filamentous-actin-structure-in-developing-neurons
#11
Xiaoqin Fu, Kristy J Brown, Chan Choo Yap, Bettina Winckler, Jyoti K Jaiswal, Judy S Liu
Doublecortin (Dcx) is the causative gene for X-linked lissencephaly, which encodes a microtubule-binding protein. Axon tracts are abnormal in both affected individuals and in animal models. To determine the reason for the axon tract defect, we performed a semiquantitative proteomic analysis of the corpus callosum in mice mutant for Dcx. In axons from mice mutant for Dcx, widespread differences are found in actin-associated proteins as compared with wild-type axons. Decreases in actin-binding proteins α-actinin-1 and α-actinin-4 and actin-related protein 2/3 complex subunit 3 (Arp3), are correlated with dysregulation in the distribution of filamentous actin (F-actin) in the mutant neurons with increased F-actin around the cell body and decreased F-actin in the neurites and growth cones...
January 9, 2013: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/22649224/doublecortin-dcx-mediates-endocytosis-of-neurofascin-independently-of-microtubule-binding
#12
Chan Choo Yap, Max Vakulenko, Kamil Kruczek, Bashir Motamedi, Laura Digilio, Judy S Liu, Bettina Winckler
Doublecortin on X chromosome (DCX) is one of two major genetic loci underlying human lissencephaly, a neurodevelopmental disorder with defects in neuronal migration and axon outgrowth. DCX is a microtubule-binding protein, and much work has focused on its microtubule-associated functions. DCX has other reported binding partners, including the cell adhesion molecule neurofascin, but the functional significance of the DCX-neurofascin interaction is not understood. Neurofascin localizes strongly to the axon initial segment in mature neurons, where it plays a role in assembling and maintaining other axon initial segment components...
May 30, 2012: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/22578496/harnessing-the-power-of-the-endosome-to-regulate-neural-development
#13
REVIEW
Chan Choo Yap, Bettina Winckler
Endocytosis and endosomal trafficking play a multitude of roles in cellular function beyond regulating entry of essential nutrients. In this review, we discuss the cell biological principles of endosomal trafficking, the neuronal adaptations to endosomal organization, and the role of endosomal trafficking in neural development. In particular, we consider how cell fate decisions, polarity, migration, and axon outgrowth and guidance are influenced by five endosomal tricks: dynamic modulation of receptor levels by endocytosis and recycling, cargo-specific responses via cargo-specific endocytic regulators, cell-type-specific endocytic regulation, ligand-specific endocytic regulation, and endosomal regulation of ligand processing and trafficking...
May 10, 2012: Neuron
https://www.readbyqxmd.com/read/21762782/mechanisms-of-polarized-membrane-trafficking-in-neurons-focusing-in-on-endosomes
#14
REVIEW
Zofia M Lasiecka, Bettina Winckler
Neurons are polarized cells that have a complex and unique morphology: long processes (axons and dendrites) extending far from the cell body. In addition, the somatodendritic and axonal domains are further divided into specific subdomains, such as synapses (pre- and postsynaptic specializations), proximal and distal dendrites, axon initial segments, nodes of Ranvier, and axon growth cones. The striking asymmetry and complexity of neuronal cells are necessary for their function in receiving, processing and transferring electrical signals, with each domain playing a precise function in these processes...
December 2011: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/21535338/endocytosis-and-endosomes-at-the-crossroads-of-regulating-trafficking-of-axon-outgrowth-modifying-receptors
#15
REVIEW
Bettina Winckler, Chan Choo Yap
In neurons, many receptors must be localized correctly to axons or dendrites for proper function. During development, receptors for nerve growth and guidance are targeted to axons and localized to growth cones where receptor activation by ligands results in promotion or inhibition of axon growth. Signaling outcomes downstream of ligand binding are determined by the location, levels and residence times of receptors on the neuronal plasma membrane. Therefore, the mechanisms controlling the trafficking of these receptors are crucial to the proper wiring of circuits...
September 2011: Traffic
https://www.readbyqxmd.com/read/21147988/neuronal-early-endosomes-require-ehd1-for-l1-ngcam-trafficking
#16
Zofia M Lasiecka, Chan Choo Yap, Steven Caplan, Bettina Winckler
In neurons, the endosomal system is essential for membrane receptor trafficking to dendrites and axons and thereby participates in various neuronal functions, such as neurite outgrowth and synaptic plasticity. A multitude of regulators coordinates trafficking through endosomes, but most of them have not been studied in detail in neurons. In non-neuronal cells, EHD1 (Eps15 homology-domain containing protein 1) functions in the recycling endosome and is required for endosome-to-plasma membrane transport of multiple cargos...
December 8, 2010: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/20921132/bettina-winckler-neuronal-polarity-on-her-mind-interviewed-by-caitlin-sedwick
#17
Bettina Winckler
No abstract text is available yet for this article.
October 4, 2010: Journal of Cell Biology
https://www.readbyqxmd.com/read/20603011/tgf-beta-receptors-par-ticipate-in-axon-formation
#18
COMMENT
Noelle D Dwyer, Bettina Winckler
How does a newborn neuron initiate and elaborate an axon? Using cutting-edge approaches, Yi et al. (2010) provide striking evidence that TGF-beta signaling via the Par polarity complex is required for axon formation by neocortical pyramidal neurons.
July 9, 2010: Cell
https://www.readbyqxmd.com/read/20504966/trafficking-guidance-receptors
#19
REVIEW
Bettina Winckler, Ira Mellman
Wiring of the brain relies initially on the correct outgrowth of axons to reach the appropriate target area for innervation. A large number of guidance receptors present in the plasma membrane of axonal growth cones and elsewhere on the neuron read and execute directional cues present in the extracellular environment of the navigating growth cone. The exact timing, levels, and localization of expression of the guidance receptors in the plasma membrane therefore determine the outcome of guidance decisions. Many guidance receptors are localized in exquisitely precise spatial and temporal patterns...
July 2010: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/20463227/alterations-of-ehd1-ehd4-protein-levels-interfere-with-l1-ngcam-endocytosis-in-neurons-and-disrupt-axonal-targeting
#20
Chan Choo C Yap, Zofia M Lasiecka, Steven Caplan, Bettina Winckler
Axon growth is regulated by many proteins, including adhesion molecules, which need to be trafficked correctly to axons. The adhesion molecule L1/neuron-glia cell adhesion molecule (NgCAM) travels to axons via an endocytosis-dependent pathway (transcytosis), traversing somatodendritic endosomes. The Eps15 homology domain (EHD) family proteins (EHD1-EHD4) play important roles in endosomal recycling and possibly in endocytosis. We investigated whether EHD1 regulates L1/NgCAM trafficking in neurons. Both short hairpin-mediated downregulation and overexpression of EHD1 led to dendritic mistargeting of NgCAM...
May 12, 2010: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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