Fred H Gage

Salk Institute, لا هویا, California, United States

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Publications (833)6913.05 Total impact

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    ABSTRACT: Rett syndrome is a severe form of autism spectrum disorder, mainly caused by mutations of a single gene methyl CpG binding protein 2 (MeCP2) on the X chromosome. Patients with Rett syndrome exhibit a period of normal development followed by regression of brain function and the emergence of autistic behaviors. However, the mechanism behind the delayed onset of symptoms is largely unknown. Here we demonstrate that neuron-specific K(+)-Cl(-) cotransporter2 (KCC2) is a critical downstream gene target of MeCP2. We found that human neurons differentiated from induced pluripotent stem cells from patients with Rett syndrome showed a significant deficit in KCC2 expression and consequently a delayed GABA functional switch from excitation to inhibition. Interestingly, overexpression of KCC2 in MeCP2-deficient neurons rescued GABA functional deficits, suggesting an important role of KCC2 in Rett syndrome. We further identified that RE1-silencing transcriptional factor, REST, a neuronal gene repressor, mediates the MeCP2 regulation of KCC2. Because KCC2 is a slow onset molecule with expression level reaching maximum later in development, the functional deficit of KCC2 may offer an explanation for the delayed onset of Rett symptoms. Our studies suggest that restoring KCC2 function in Rett neurons may lead to a potential treatment for Rett syndrome.
    Full-text · Article · Jan 2016 · Proceedings of the National Academy of Sciences
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    Full-text · Article · Jan 2016 · Molecular Psychiatry
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    ABSTRACT: Primary afferent collateral sprouting is a process whereby non-injured primary afferent neurons respond to some stimulus and extend new branches from existing axons. Neurons of both the central and peripheral nervous systems undergo this process, which contributes to both adaptive and maladaptive plasticity (e.g., [1-9]). In the model used here (the "spared dermatome" model), the intact sensory neurons respond to the denervation of adjacent areas of skin by sprouting new axon branches into that adjacent denervated territory. Investigations of gene expression changes associated with collateral sprouting can provide a better understanding of the molecular mechanisms controlling this process. Consequently, it can be used to develop treatments to promote functional recovery for spinal cord injury and other similar conditions. This report includes raw gene expression data files from microarray experiments in order to study the gene regulation in spared sensory ganglia in the initiation (7 days) and maintenance (14 days) phases of the spared dermatome model relative to intact ("naïve") sensory ganglia. Data has been deposited into GEO (GSE72551).
    Full-text · Article · Dec 2015 · Genomics Data
  • Anindita Sarkar · Maria C. Marchetto · Fred H. Gage
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    ABSTRACT: Schizophrenia is a polygenic disorder with a complex etiology. While the genetic and molecular underpinnings of the disease are poorly understood, variations in genes encoding synaptic pathways are consistently implicated. Although its impact is still an open question, a deficit in synaptic activity provides an attractive model to explain the cognitive etiology of schizophrenia. Recent advances in high-throughput imaging and functional studies bring new hope for the application of in vitro disease modeling with patient-derived neurons to empirically ascertain the extent to which these synaptic pathways are involved in the disease. In addition, the emergent avenue of research targeted to probe neuronal connections is revealing critical insight into circuitry and may influence how we think about psychiatric disorders in the near future.
    No preview · Article · Dec 2015 · Brain research
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    Fred H. Gage

    Preview · Article · Dec 2015 · Daedalus
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    ABSTRACT: There is an urgent need for a therapy that reverses disability after stroke when initiated in a time frame suitable for the majority of new victims. We show here that intramuscular delivery of neurotrophin-3 (NT3, encoded by NTF3) can induce sensorimotor recovery when treatment is initiated 24 h after stroke. Specifically, in two randomized, blinded preclinical trials, we show improved sensory and locomotor function in adult (6 months) and elderly (18 months) rats treated 24 h following cortical ischaemic stroke with human NT3 delivered using a clinically approved serotype of adeno-associated viral vector (AAV1). Importantly, AAV1-hNT3 was given in a clinically-feasible timeframe using a straightforward, targeted route (injections into disabled forelimb muscles). Magnetic resonance imaging and histology showed that recovery was not due to neuroprotection, as expected given the delayed treatment. Rather, treatment caused corticospinal axons from the less affected hemisphere to sprout in the spinal cord. This treatment is the first gene therapy that reverses disability after stroke when administered intramuscularly in an elderly body. Importantly, phase I and II clinical trials by others show that repeated, peripherally administered high doses of recombinant NT3 are safe and well tolerated in humans with other conditions. This paves the way for NT3 as a therapy for stroke.
    No preview · Article · Nov 2015 · Brain
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    ABSTRACT: Hippocampal adult neurogenesis is thought to subserve pattern separation, the process by which similar patterns of neuronal inputs are transformed into distinct neuronal representations, permitting the discrimination of highly similar stimuli in hippocampus-dependent tasks. However, the mechanism by which immature adult-born dentate granule neurons cells (abDGCs) perform this function remains unknown. Two theories of abDGC function, one by which abDGCs modulate and sparsify activity in the dentate gyrus and one by which abDGCs act as autonomous coding units, are generally suggested to be mutually exclusive. This review suggests that these two mechanisms work in tandem to dynamically regulate memory resolution while avoiding memory interference and maintaining memory robustness.
    Full-text · Article · Nov 2015 · Neurobiology of Learning and Memory
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    ABSTRACT: RE-1 silencing transcription factor (REST), a master negative regulator of neuronal differentiation, controls neurogenesis by preventing the differentiation of neural stem cells. Here we focused on the role of REST in the early steps of differentiation and maturation of adult hippocampal progenitors (AHPs). REST knockdown promoted differentiation and affected the maturation of rat AHPs. Surprisingly, REST knockdown cells enhanced the differentiation of neighboring wild-type AHPs, suggesting that REST may play a non-cellautonomous role. Gene expression analysis identified Secretogranin II (Scg2) as the major secreted REST target responsible for the non-cell-autonomous phenotype. Loss-of-function of Scg2 inhibited differentiation in vitro, and exogenous SCG2 partially rescued this phenotype. Knockdown of REST in neural progenitors in mice led to precocious maturation into neurons at the expense of mushroom spines in vivo. In summary, we found that, in addition to its cell-autonomous function, REST regulates differentiation and maturation of AHPs non-cell-autonomously via SCG2.
    No preview · Article · Nov 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.
    Full-text · Article · Nov 2015 · Nature
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    ABSTRACT: As a group, we met to discuss the current challenges for creating meaningful patient-specific in vitro models to study brain disorders. Although the convergence of findings between laboratories and patient cohorts provided us confidence and optimism that hiPSC-based platforms will inform future drug discovery efforts, a number of critical technical challenges remain. This opinion piece outlines our collective views on the current state of hiPSC-based disease modeling and discusses what we see to be the critical objectives that must be addressed collectively as a field.
    Full-text · Article · Nov 2015 · Stem Cell Reports
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    ABSTRACT: The brain's serotonergic system centrally regulates several physiological processes and its dysfunction has been implicated in the pathophysiology of several neuropsychiatric disorders. While in the past our understanding of serotonergic neurotransmission has come mainly from mouse models, the development of pluripotent stem cell and induced fibroblast-to-neuron (iN) transdifferentiation technologies has revolutionized our ability to generate human neurons in vitro. Utilizing these techniques and a novel lentiviral reporter for serotonergic neurons, we identified and overexpressed key transcription factors to successfully generate human serotonergic neurons. We found that overexpressing the transcription factors NKX2.2, FEV, GATA2 and LMX1B in combination with ASCL1 and NGN2 directly and efficiently generated serotonergic neurons from human fibroblasts. Induced serotonergic neurons (iSNs) showed increased expression of specific serotonergic genes that are known to be expressed in raphe nuclei. iSNs displayed spontaneous action potentials, released serotonin in vitro and functionally responded to selective serotonin reuptake inhibitors (SSRIs). Here, we demonstrate the efficient generation of functional human serotonergic neurons from human fibroblasts as a novel tool for studying human serotonergic neurotransmission in health and disease.Molecular Psychiatry advance online publication, 27 October 2015; doi:10.1038/mp.2015.161.
    Full-text · Article · Oct 2015 · Molecular Psychiatry
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    ABSTRACT: LINE-1 retrotransposons are fast-evolving mobile genetic entities that play roles in gene regulation, pathological conditions, and evolution. Here, we show that the primate LINE-1 50UTR contains a pri- mate-specific open reading frame (ORF) in the anti- sense orientation that we named ORF0. The gene product of this ORF localizes to promyelocytic leuke- mia-adjacent nuclear bodies. ORF0 is present in more than 3,000 loci across human and chimpanzee genomes and has a promoter and a conserved strong Kozak sequence that supports translation. By virtue of containing two splice donor sites, ORF0 can also form fusion proteins with proximal exons. ORF0 transcripts are readily detected in induced pluripotent stem (iPS) cells from both pri- mate species. Capped and polyadenylated ORF0 mRNAs are present in the cytoplasm, and endoge- nous ORF0 peptides are identified upon proteomic analysis. Finally, ORF0 enhances LINE-1 mobility. Taken together, these results suggest a role for ORF0 in retrotransposon-mediated diversity.
    Full-text · Article · Oct 2015 · Cell
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    Yangling Mu · Chunmei Zhao · Nicolas Toni · Jun Yao · Fred H Gage
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    ABSTRACT: NMDA receptor (NMDAR)-dependent forms of synaptic plasticity are thought to underlie the assembly of developing neuronal circuits and to play a crucial role in learning and memory. It remains unclear how NMDAR might contribute to the wiring of adult-born granule cells (GCs). Here we demonstrate that nascent GCs lacking NMDARs but rescued from apoptosis by overexpressing the pro-survival protein Bcl2 were deficient in spine formation. Insufficient spinogenesis might be a general cause of cell death restricted within the NMDAR-dependent critical time window for GC survival. NMDAR loss also led to enhanced mushroom spine formation and synaptic AMPAR activity throughout the development of newborn GCs. Moreover, similar elevated synapse maturation in the absence of NMDARs was observed in neonate-generated GCs and CA1 pyramidal neurons. Together, these data suggest that NMDAR operates as a molecular monitor for controlling the activity-dependent establishment and maturation rate of synaptic connections between newborn neurons and others.
    Full-text · Article · Oct 2015 · eLife Sciences
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    ABSTRACT: Aging is a major risk factor for many human diseases, and in vitro generation of human neurons is an attractive approach for modeling aging-related brain disorders. However, modeling aging in differentiated human neurons has proved challenging. We generated neurons from human donors across a broad range of ages, either by iPSC-based reprogramming and differentiation or by direct conversion into induced neurons (iNs). While iPSCs and derived neurons did not retain aging-associated gene signatures, iNs displayed age-specific transcriptional profiles and revealed age-associated decreases in the nuclear transport receptor RanBP17. We detected an age-dependent loss of nucleocytoplasmic compartmentalization (NCC) in donor fibroblasts and corresponding iNs and found that reduced RanBP17 impaired NCC in young cells, while iPSC rejuvenation restored NCC in aged cells. These results show that iNs retain important aging-related signatures, thus allowing modeling of the aging process in vitro, and they identify impaired NCC as an important factor in human aging.
    Full-text · Article · Oct 2015 · Cell stem cell
  • Ayumu Tashiro · Chunmei Zhao · Hoonkyo Suh · Fred H. Gage
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    ABSTRACT: Retroviral vectors are a powerful technology for achieving long-term genetic manipulation. This introduction provides some background on replication-deficient retroviral vectors based on Moloney murine leukemia virus and lentivirus. Details, examples, and associated protocols are provided for using these vectors to fluorescently label, genetically alter, and image both live and fixed murine brain tissue.
    No preview · Article · Oct 2015
  • Ayumu Tashiro · Chunmei Zhao · Hoonkyo Suh · Fred H. Gage
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    ABSTRACT: Retroviral vectors are powerful tools for genetic manipulation. This protocol discusses the production, purification, and use of replication-deficient retroviral vectors based on Moloney murine leukemia virus and lentivirus. It also describes the injection of a retroviral vector into the dentate gyrus of young adult mice to fluorescently label live murine brain tissue.
    No preview · Article · Oct 2015
  • Ayumu Tashiro · Chunmei Zhao · Hoonkyo Suh · Fred H. Gage
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    ABSTRACT: This protocol describes the harvesting of brain tissue from mice that have had the retroviral vector CAG-GFP injected into the dentate gyrus. Brain tissue from these mice is dissected, the tissue is fixed, and the sections are prepared. The fixed sections are imaged using fluorescent confocal microscopy, and newborn granule cells containing GFP are visualized and are characterized.
    No preview · Article · Oct 2015
  • Ayumu Tashiro · Chunmei Zhao · Hoonkyo Suh · Fred H. Gage
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    ABSTRACT: In this protocol, acute brain slices are prepared from mice in which newborn granule cells have been labeled using retroviral vector technology. Using a live-cell imaging stage and confocal microscopy coupled to imaging software, dendritic spines are analyzed.
    No preview · Article · Oct 2015
  • Gerd Kempermann · Hongjun Song · Fred H. Gage
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    ABSTRACT: Of the neurogenic zones in the adult brain, adult hippocampal neurogenesis attracts the most attention, because it is involved in higher cognitive function, most notably memory processes, and certain affective behaviors. Adult hippocampal neurogenesis is also found in humans at a considerable level and appears to contribute significantly to hippocampal plasticity across the life span, because it is regulated by activity. Adult hippocampal neurogenesis generates new excitatory granule cells in the dentate gyrus, whose axons form the mossy fiber tract that links the dentate gyrus to CA3. It originates from a population of radial glia-like precursor cells (type 1 cells) that have astrocytic properties, express markers of neural stem cells and divide rarely. They give rise to intermediate progenitor cells with first glial (type 2a) and then neuronal (type 2b) phenotype. Through a migratory neuroblast-like stage (type 3), the newborn, lineage-committed cells exit the cell cycle and enter a maturation stage, during which they extend their dendrites into a the molecular layer and their axon to CA3. They go through a period of several weeks, during which they show increased synaptic plasticity, before finally becoming indistinguishable from the older granule cells. © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    No preview · Article · Sep 2015 · Cold Spring Harbor Perspectives in Medicine
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    ABSTRACT: cis-regulatory changes play a central role in mor- phological divergence, yet the regulatory principles underlying emergence of human traits remain poorly understood. Here, we use epigenomic profiling from human and chimpanzee cranial neural crest cells to systematically and quantitatively annotate diver- gence of craniofacial cis-regulatory landscapes. Epi- genomic divergence is often attributable to genetic variation within TF motifs at orthologous enhancers, with a novel motif being most predictive of activity biases. We explore properties of this cis-regulatory change, revealing the role of particular retroele- ments, uncovering broad clusters of species-biased enhancers near genes associated with human facial variation, and demonstrating that cis-regulatory divergence is linked to quantitative expression differ- ences of crucial neural crest regulators. Our work provides a wealth of candidates for future evolu- tionary studies and demonstrates the value of ‘‘cellular anthropology,’’ a strategy of using in-vitro- derived embryonic cell types to elucidate both fundamental and evolving mechanisms underlying morphological variation in higher primates
    Full-text · Article · Sep 2015 · Cell

Publication Stats

112k Citations
6,913.05 Total Impact Points

Institutions

  • 1970-2015
    • Salk Institute
      • Laboratory of Genetics
      لا هویا, California, United States
  • 1997-2014
    • Torrey Pines Institute for Molecular Studies
      Port St. Lucie, Florida, United States
  • 2013
    • University of Lausanne
      Lausanne, Vaud, Switzerland
  • 1986-2013
    • University of California, San Diego
      • • Department of Neurosciences
      • • Department of Medicine
      San Diego, California, United States
    • Colorado State University
      • Department of Anatomy and Neurobiology
      Fort Collins, Colorado, United States
    • University of Oxford
      • Department of Pharmacology
      Oxford, England, United Kingdom
  • 1996-2008
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 1982-2008
    • Lund University
      • • Division of Neurology
      • • Department of Surgery
      Lund, Skåne, Sweden
  • 2006
    • King's College London
      • Centre for the Cellular Basis of Behaviour
      London, ENG, United Kingdom
  • 2004
    • Fundación Instituto Leloir
      Buenos Aires, Buenos Aires F.D., Argentina
    • Kumamoto University
      Kumamoto, Kumamoto, Japan
  • 2003
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 2002
    • University of Washington Seattle
      • Department of Neurological Surgery
      Seattle, Washington, United States
  • 2001
    • Stanford University
      Stanford, California, United States
  • 2000
    • Princeton University
      Princeton, New Jersey, United States
  • 1998
    • Sahlgrenska University Hospital
      • Department of Cardiology
      Goeteborg, Västra Götaland, Sweden
  • 1991-1992
    • University of California, San Francisco
      • Department of Neurology
      San Francisco, CA, United States
    • Neuropsychiatric Research Institute
      Fargo, North Dakota, United States
  • 1974-1991
    • Johns Hopkins University
      • Department of Neuroscience
      Baltimore, Maryland, United States
  • 1990
    • University of San Diego
      San Diego, California, United States
  • 1989
    • CSU Mentor
      Long Beach, California, United States
  • 1988
    • Karolinska Institutet
      • Department of Neuroscience
      Сольна, Stockholm, Sweden
  • 1978-1984
    • Texas Christian University
      • Department of Psychology
      Fort Worth, Texas, United States