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david ginty

Mengchen Ye, Kathryn M Lehigh, David D Ginty
The development of neurons in the peripheral nervous system is dependent on target-derived, long-range retrograde neurotrophic factor signals. The prevailing view is that target-derived nerve growth factor (NGF), the prototypical neurotrophin, and its receptor TrkA are carried retrogradely by early endosomes, which serve as TrkA signaling platforms in cell bodies. Here, we report that the majority of retrograde TrkA signaling endosomes in mouse sympathetic neurons are ultrastructurally and molecularly defined multivesicular bodies (MVBs)...
January 30, 2018: ELife
Qiang Wang, Shu-Ling Chiu, Eleftheria Koropouli, Ingie Hong, Sarah Mitchell, Teresa P Easwaran, Natalie R Hamilton, Ahleah S Gustina, Qianwen Zhu, David D Ginty, Richard L Huganir, Alex L Kolodkin
Regulation of AMPA-type glutamate receptor (AMPAR) number at synapses is a major mechanism for controlling synaptic strength during homeostatic scaling in response to global changes in neural activity. We show that the secreted guidance cue semaphorin 3F (Sema3F) and its neuropilin-2 (Npn-2)/plexinA3 (PlexA3) holoreceptor mediate homeostatic plasticity in cortical neurons. Sema3F-Npn-2/PlexA3 signaling is essential for cell surface AMPAR homeostatic downscaling in response to an increase in neuronal activity, Npn-2 associates with AMPARs, and Sema3F regulates this interaction...
December 6, 2017: Neuron
Liam E Browne, Alban Latremoliere, Brendan P Lehnert, Alyssa Grantham, Catherine Ward, Chloe Alexandre, Michael Costigan, Frédéric Michoud, David P Roberson, David D Ginty, Clifford J Woolf
Potentially harmful stimuli are detected at the skin by nociceptor sensory neurons that drive rapid protective withdrawal reflexes and pain. We set out to define, at a millisecond timescale, the relationship between the activity of these sensory neurons and the resultant behavioral output. Brief optogenetic activation of cutaneous nociceptors was found to activate only a single action potential in each fiber. This minimal input was used to determine high-speed behavioral responses in freely behaving mice. The localized stimulus generated widespread dynamic repositioning and alerting sub-second behaviors whose nature and timing depended on the context of the animal and its position, activity, and alertness...
July 5, 2017: Cell Reports
Kyle S Severson, Duo Xu, Margaret Van de Loo, Ling Bai, David D Ginty, Daniel H O'Connor
Touch perception depends on integrating signals from multiple types of peripheral mechanoreceptors. Merkel-cell associated afferents are thought to play a major role in form perception by encoding surface features of touched objects. However, activity of Merkel afferents during active touch has not been directly measured. Here, we show that Merkel and unidentified slowly adapting afferents in the whisker system of behaving mice respond to both self-motion and active touch. Touch responses were dominated by sensitivity to bending moment (torque) at the base of the whisker and its rate of change and largely explained by a simple mechanical model...
May 3, 2017: Neuron
Benjamin J Andreone, Brian Wai Chow, Aleksandra Tata, Baptiste Lacoste, Ayal Ben-Zvi, Kevin Bullock, Amy A Deik, David D Ginty, Clary B Clish, Chenghua Gu
The blood-brain barrier (BBB) provides a constant homeostatic brain environment that is essential for proper neural function. An unusually low rate of vesicular transport (transcytosis) has been identified as one of the two unique properties of CNS endothelial cells, relative to peripheral endothelial cells, that maintain the restrictive quality of the BBB. However, it is not known how this low rate of transcytosis is achieved. Here we provide a mechanism whereby the regulation of CNS endothelial cell lipid composition specifically inhibits the caveolae-mediated transcytotic route readily used in the periphery...
May 3, 2017: Neuron
Kathryn M Lehigh, Katherine M West, David D Ginty
Sympathetic neurons require NGF from their target fields for survival, axonal target innervation, dendritic growth and formation, and maintenance of synaptic inputs from preganglionic neurons. Target-derived NGF signals are propagated retrogradely, from distal axons to somata of sympathetic neurons via TrkA signaling endosomes. We report that a subset of TrkA endosomes that are transported from distal axons to cell bodies translocate into dendrites, where they are signaling competent and move bidirectionally, in close proximity to synaptic protein clusters...
April 4, 2017: Cell Reports
Victoria E Abraira, Emily D Kuehn, Anda M Chirila, Mark W Springel, Alexis A Toliver, Amanda L Zimmerman, Lauren L Orefice, Kieran A Boyle, Ling Bai, Bryan J Song, Karleena A Bashista, Thomas G O'Neill, Justin Zhuo, Connie Tsan, Jessica Hoynoski, Michael Rutlin, Laura Kus, Vera Niederkofler, Masahiko Watanabe, Susan M Dymecki, Sacha B Nelson, Nathaniel Heintz, David I Hughes, David D Ginty
The deep dorsal horn is a poorly characterized spinal cord region implicated in processing low-threshold mechanoreceptor (LTMR) information. We report an array of mouse genetic tools for defining neuronal components and functions of the dorsal horn LTMR-recipient zone (LTMR-RZ), a role for LTMR-RZ processing in tactile perception, and the basic logic of LTMR-RZ organization. We found an unexpectedly high degree of neuronal diversity in the LTMR-RZ: seven excitatory and four inhibitory subtypes of interneurons exhibiting unique morphological, physiological, and synaptic properties...
January 12, 2017: Cell
Lauren L Orefice, Amanda L Zimmerman, Anda M Chirila, Steven J Sleboda, Joshua P Head, David D Ginty
Patients with autism spectrum disorders (ASDs) commonly experience aberrant tactile sensitivity, yet the neural alterations underlying somatosensory dysfunction and the extent to which tactile deficits contribute to ASD characteristics are unknown. We report that mice harboring mutations in Mecp2, Gabrb3, Shank3, and Fmr1 genes associated with ASDs in humans exhibit altered tactile discrimination and hypersensitivity to gentle touch. Deletion of Mecp2 or Gabrb3 in peripheral somatosensory neurons causes mechanosensory dysfunction through loss of GABAA receptor-mediated presynaptic inhibition of inputs to the CNS...
July 14, 2016: Cell
Lik Hang Lee, Eran Sadot, Sinisa Ivelja, Efsevia Vakiani, Jaclyn F Hechtman, Christopher J Sevinsky, David S Klimstra, Fiona Ginty, Jinru Shia
ARID1A is a chromatin remodeling gene that is mutated in a number of cancers including colorectal carcinoma (CRC). Loss of ARID1A has been associated with an adverse outcome in some types of cancer. However, literature data have not been consistent. Major limitations of some outcome studies include small sample size and heterogeneous patient population. In this study, we evaluated the prognostic value of ARID1A in a homogeneous group of early stage CRC patients, a population where prognostic markers are particularly relevant...
July 2016: Human Pathology
Ling Bai, Brendan P Lehnert, Junwei Liu, Nicole L Neubarth, Travis L Dickendesher, Pann H Nwe, Colleen Cassidy, C Jeffery Woodbury, David D Ginty
Touch perception begins with activation of low-threshold mechanoreceptors (LTMRs) in the periphery. LTMR terminals exhibit tremendous morphological heterogeneity that specifies their mechanical receptivity. In a survey of mammalian skin, we found a preponderance of neurofilament-heavy-chain(+) circumferential endings associated with hair follicles, prompting us to develop a genetic strategy to interrogate these neurons. Targeted in vivo recordings revealed them to be Aβ field-LTMRs, identified 50 years ago but largely elusive thereafter...
December 17, 2015: Cell
Ryan C Brindle, Annie T Ginty, Anna C Phillips, James P Fisher, David McIntyre, Douglas Carroll
Correlation dimension (D2), a measure of heart rate (HR) complexity, has been shown to decrease in response to acute mental stress and relate to adverse cardiovascular health. However, the relationship between stress-induced changes in D2 and HR has yet to be established. The present studies aimed to assess this relationship systematically while controlling for changes in respiration and autonomic activity. In Study 1 (N = 25) D2 decreased during stress and predicted HR reactivity even after adjusting for changes in respiration rate, and cardiac vagal tone...
April 2016: Psychophysiology
Siyi Huang, Kevin J O'Donovan, Eric E Turner, Jian Zhong, David D Ginty
The generation of diverse neuronal subtypes involves specification of neural progenitors and, subsequently, postmitotic neuronal differentiation, a relatively poorly understood process. Here, we describe a mechanism whereby the neurotrophic factor NGF and the transcription factor Runx1 coordinate postmitotic differentiation of nonpeptidergic nociceptors, a major nociceptor subtype. We show that the integrity of a Runx1/CBFβ holocomplex is crucial for NGF-dependent nonpeptidergic nociceptor maturation. NGF signals through the ERK/MAPK pathway to promote expression of Cbfb but not Runx1 prior to maturation of nonpeptidergic nociceptors...
September 29, 2015: ELife
Michael Rutlin, Cheng-Ying Ho, Victoria E Abraira, Colleen Cassidy, Ling Bai, C Jeffery Woodbury, David D Ginty
The perception of touch, including the direction of stimulus movement across the skin, begins with activation of low-threshold mechanosensory neurons (LTMRs) that innervate the skin. Here, we show that murine Aδ-LTMRs are preferentially tuned to deflection of body hairs in the caudal-to-rostral direction. This tuning property is explained by the finding that Aδ-LTMR lanceolate endings around hair follicles are polarized; they are concentrated on the caudal (downward) side of each hair follicle. The neurotrophic factor BDNF is synthesized in epithelial cells on the caudal, but not rostral, side of hair follicles, in close proximity to Aδ-LTMR lanceolate endings, which express TrkB...
December 18, 2014: Cell
Paul Hourd, Amit Chandra, David Alvey, Patrick Ginty, Mark McCall, Elizabeth Ratcliffe, Erin Rayment, David J Williams
Academic centers, hospitals and small companies, as typical development settings for UK regenerative medicine assets, are significant contributors to the development of autologous cell-based therapies. Often lacking the appropriate funding, quality assurance heritage or specialist regulatory expertise, qualifying aseptic cell processing facilities for GMP compliance is a significant challenge. The qualification of a new Cell Therapy Manufacturing Facility with automated processing capability, the first of its kind in a UK academic setting, provides a unique demonstrator for the qualification of small-scale, automated facilities for GMP-compliant manufacture of autologous cell-based products in these settings...
2014: Regenerative Medicine
Amanda Zimmerman, Ling Bai, David D Ginty
The skin is our largest sensory organ, transmitting pain, temperature, itch, and touch information to the central nervous system. Touch sensations are conveyed by distinct combinations of mechanosensory end organs and the low-threshold mechanoreceptors (LTMRs) that innervate them. Here we explore the various structures underlying the diverse functions of cutaneous LTMR end organs. Beyond anchoring of LTMRs to the surrounding dermis and epidermis, recent evidence suggests that the non-neuronal components of end organs play an active role in signaling to LTMRs and may physically gate force-sensitive channels in these receptors...
November 21, 2014: Science
Kenji Mandai, Dorothy V Reimert, David D Ginty
During the development of forebrain connectivity, ascending thalamocortical and descending corticofugal axons first intermingle at the pallial-subpallial boundary to form the internal capsule (IC). However, the identity of molecular cues that guide these axons remains largely unknown. Here, we show that the transmembrane protein Linx is robustly expressed in the prethalamus and lateral ganglionic eminence-derived corridor and on corticofugal axons, but not on thalamocortical axons, and that mice with a null mutation of Linx exhibit a complete absence of the IC...
July 2, 2014: Neuron
Paul Hourd, Patrick Ginty, Amit Chandra, David J Williams
Manufacturing of more-than-minimally manipulated autologous cell therapies presents a number of unique challenges driven by complex supply logistics and the need to scale out production to multiple manufacturing sites or near the patient within hospital settings. The existing regulatory structure in Europe and the United States imposes a requirement to establish and maintain comparability between sites. Under a single market authorization, this is likely to become an unsurmountable burden beyond two or three sites...
August 2014: Cytotherapy
Lishi Li, David D Ginty
In mouse hairy skin, lanceolate complexes associated with three types of hair follicles, guard, awl/auchene and zigzag, serve as mechanosensory end organs. These structures are formed by unique combinations of low-threshold mechanoreceptors (LTMRs), Aβ RA-LTMRs, Aδ-LTMRs, and C-LTMRs, and their associated terminal Schwann cells (TSCs). In this study, we investigated the organization, ultrastructure, and maintenance of longitudinal lanceolate complexes at each hair follicle subtype. We found that TSC processes at hair follicles are tiled and that individual TSCs host axonal endings of more than one LTMR subtype...
2014: ELife
Caitlin Engelhard, Sarah Sarsfield, Janna Merte, Qiang Wang, Peng Li, Hideyuki Beppu, Alex L Kolodkin, Henry M Sucov, David D Ginty
Bone morphogenetic protein (BMP) signaling has emerged as an important regulator of sensory neuron development. Using a three-generation forward genetic screen in mice we have identified Megf8 as a novel modifier of BMP4 signaling in trigeminal ganglion (TG) neurons. Loss of Megf8 disrupts axon guidance in the peripheral nervous system and leads to defects in development of the limb, heart, and left-right patterning, defects that resemble those observed in Bmp4 loss-of-function mice. Bmp4 is expressed in a pattern that defines the permissive field for the peripheral projections of TG axons and mice lacking BMP signaling in sensory neurons exhibit TG axon defects that resemble those observed in Megf8 (-/-) embryos...
2013: ELife
Francois-Pierre J Martin, Ivan Montoliu, Sebastiano Collino, Max Scherer, Philippe Guy, Isabelle Tavazzi, Anita Thorimbert, Sofia Moco, Megan P Rothney, David L Ergun, Maurice Beaumont, Fiona Ginty, Salah D Qanadli, Lucie Favre, Vittorio Giusti, Serge Rezzi
Visceral adiposity is increasingly recognized as a key condition for the development of obesity related disorders, with the ratio between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) reported as the best correlate of cardiometabolic risk. In this study, using a cohort of 40 obese females (age: 25-45 y, BMI: 28-40 kg/m(2)) under healthy clinical conditions and monitored over a 2 weeks period we examined the relationships between different body composition parameters, estimates of visceral adiposity and blood/urine metabolic profiles...
2013: PloS One
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