Michael E. Greenberg

Last updated
Michael E. Greenberg
Born (1954-05-25) May 25, 1954 (age 70)
Nationality American
Alma mater Wesleyan University, Rockefeller University
Known for Molecular neuroscience, c-fos
Awards Perl-UNC Prize (2008)
Scientific career
Fields Neurobiology
Institutions Harvard Medical School
Doctoral advisor Gerald Edelman
Website http://greenberg.hms.harvard.edu/

Michael Greenberg (born May 25, 1954 in Miami Beach, Florida) is an American neuroscientist who specializes in molecular neurobiology. [1] He served as the Chair of the Department of Neurobiology at Harvard Medical School from 2008 to 2022.

Contents

Biography

Michael Greenberg grew up in Brooklyn, New York and graduated from Wesleyan University (magna cum laude) in 1976 with a degree in chemistry. He conducted his Ph.D. research and began his post-doctoral research at Rockefeller University in New York City in the laboratory of Nobel Laureate Gerald Edelman. He later completed his postdoctoral research with Edward Ziff at New York University Medical Center.

During his time in Ziff's lab, Greenberg observed that the transcription of c-fos, a cellular proto-oncogene, is induced within minutes of activation by neurotrophic factors, one of the first mechanistic descriptions of how cells respond to external signals. This finding in cell culture led to the observation that neuronal activity and even sensory experience can induce c-fos expression in the brain; this finding is now considered a principal tenet in neurobiology, and is widely used in neuroscience as a bona fide marker of active neurons. The Nobel Prize-winning experiments of Torsten Wiesel and David Hubel in the 1960s showed that visual experience is required during development to establish proper circuitry in the visual cortex, however the cellular and molecular basis for this was unknown. The identification of c-fos, and other activity-dependent genes, provided a molecular mechanism that explained how experience (i.e. nurture) can be coupled with a cellular process (i.e. nature).

In 1986, Greenberg moved to Boston, Massachusetts to start his lab in the Department of Microbiology and Molecular Genetics at Harvard Medical School. In 1999, he was named Director of the Neurobiology Program at Boston Children's Hospital. [2] [3] In 2008, he became the Department Chair of the Department of Neurobiology at Harvard Medical School. [4]

The mission of the Greenberg lab is to understand the mechanisms by which the activity-dependent gene expression program regulates brain development and function. [5] Work from the lab has characterized many of the fundamental steps in this process, from the initial activation of ion channels that depolarize neurons, [6] [7] the subsequent downstream signaling cascade [8] that culminates in gene expression, and the pattern of experience-dependent gene expression in particular subtypes of cells in the brain, such as inhibitory versus excitatory neurons. [9]

The activity-dependent gene expression program discovered by Greenberg has been shown to play an important biological role in nervous system development and function, specifically in the formation of inhibitory circuits in the brain. Greenberg and colleagues showed that through introduction of a mutation in a particular site in the promoter of the activity-dependent gene, Bdnf , visual experience was unable to induce Bdnf expression in the cortex of mice. Moreover, the authors found that the formation of inhibitory synapses and circuits was disrupted in these animals. [10] The authors found no effect in excitatory synapse formation or function.

In addition to this finding, the Greenberg lab also discovered NPAS4, an activity-dependent transcription factor that is required for inhibitory synapse formation through its regulation of Bdnf transcription, and other activity-dependent genes. [11] Similar to their previous finding, the authors found a specific role for this genetic program in inhibitory circuit development, since perturbation of NPAS4 function had no effect in excitatory synapse formation or function. Thus, the activity-dependent gene program plays a key role specifically in the development of inhibitory circuits in the cortex, which are responsible for fine-tuning neuronal output and nervous system function.

In 2010, the Greenberg lab discovered a new class of RNAs called enhancer RNAs (eRNA), RNAs that are transcribed from enhancer regions of chromosomes. [12] Greenberg and colleagues found that eRNAs are transcribed in response to neuronal activity, and function to control the expression of other genes in cells. The role of eRNAs in regulating gene expression in health and disease is continuing to be explored in various fields, such as cancer research.

His research has also explored the molecular biology and genetics of autism spectrum disorders, specifically in Rett Syndrome, a disease that is caused by mutations in MeCP2, a methyl-DNA binding protein that regulates transcription. His studies have examined the experience-dependent gene program in mouse models of Rett Syndrome, and specifically, how mutations in MeCP2 disrupt the expression of particularly long genes in the brain. [13]

The Greenberg lab is also studying activity-dependent gene expression in human neurons, and is comparing this program of gene expression to other mammals and other primates. In 2016, he and his colleagues identified a gene that is selectively induced in human and primate brains following stimulation. [14] They found that the gene, called osteocrin, while expressed in mouse bone and muscle, is not detected in rodent brains, and that its inducible expression in primate neurons is conferred by the evolution of DNA regulatory elements that bind the activity-dependent transcription factor, MEF2.

Greenberg is the author of more than 200 articles and serves on the editorial boards of the following journals, among others: Journal of Neuroscience ; Learning & Memory ; Neuron ; and Molecular & Cellular Neuroscience . [15] [16] He has mentored a number of successful neuroscientists, including Morgan Sheng, David Ginty, Azad Bonni, Anne Brunet, Ricardo Dolmetsch, Anirvan Ghosh, and Hilmar Bading.

Greenberg has received numerous prizes, including the Edward M. Scolnick Prize in Neuroscience, and a McKnight award for technological advances in neuroscience. In 2015, he was awarded the Gruber Prize in Neuroscience, along with Carla Shatz. He is a member of the American Academy of Arts and Sciences and of the National Academy of Sciences. [17] In 2023 he received The Brain Prize. [18]

Related Research Articles

The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field of neural development draws on both neuroscience and developmental biology to describe and provide insight into the cellular and molecular mechanisms by which complex nervous systems develop, from nematodes and fruit flies to mammals.

<span class="mw-page-title-main">Brain-derived neurotrophic factor</span> Protein found in humans

Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factor (NGF), a family which also includes NT-3 and NT-4/NT-5. Neurotrophic factors are found in the brain and the periphery. BDNF was first isolated from a pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.

Immediate early genes (IEGs) are genes which are activated transiently and rapidly in response to a wide variety of cellular stimuli. They represent a standing response mechanism that is activated at the transcription level in the first round of response to stimuli, before any new proteins are synthesized. IEGs are distinct from "late response" genes, which can only be activated later, following the synthesis of early response gene products. Thus IEGs have been called the "gateway to the genomic response". The term can describe viral regulatory proteins that are synthesized following viral infection of a host cell, or cellular proteins that are made immediately following stimulation of a resting cell by extracellular signals.

Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenesis. Synaptogenesis is particularly important during an individual's critical period, during which there is a certain degree of synaptic pruning due to competition for neural growth factors by neurons and synapses. Processes that are not used, or inhibited during their critical period will fail to develop normally later on in life.

Molecular neuroscience is a branch of neuroscience that observes concepts in molecular biology applied to the nervous systems of animals. The scope of this subject covers topics such as molecular neuroanatomy, mechanisms of molecular signaling in the nervous system, the effects of genetics and epigenetics on neuronal development, and the molecular basis for neuroplasticity and neurodegenerative diseases. As with molecular biology, molecular neuroscience is a relatively new field that is considerably dynamic.

<span class="mw-page-title-main">Silencer (genetics)</span> Type of DNA sequence

In genetics, a silencer is a DNA sequence capable of binding transcription regulation factors, called repressors. DNA contains genes and provides the template to produce messenger RNA (mRNA). That mRNA is then translated into proteins. When a repressor protein binds to the silencer region of DNA, RNA polymerase is prevented from transcribing the DNA sequence into RNA. With transcription blocked, the translation of RNA into proteins is impossible. Thus, silencers prevent genes from being expressed as proteins.

Anirvan Ghosh is an American neuroscientist and Biotech executive.

<span class="mw-page-title-main">Chloride potassium symporter 5</span> Protein-coding gene in the species Homo sapiens

Potassium-chloride transporter member 5 is a neuron-specific chloride potassium symporter responsible for establishing the chloride ion gradient in neurons through the maintenance of low intracellular chloride concentrations. It is a critical mediator of synaptic inhibition, cellular protection against excitotoxicity and may also act as a modulator of neuroplasticity. Potassium-chloride transporter member 5 is also known by the names: KCC2 for its ionic substrates, and SLC12A5 for its genetic origin from the SLC12A5 gene in humans.

Activity-dependent plasticity is a form of functional and structural neuroplasticity that arises from the use of cognitive functions and personal experience; hence, it is the biological basis for learning and the formation of new memories. Activity-dependent plasticity is a form of neuroplasticity that arises from intrinsic or endogenous activity, as opposed to forms of neuroplasticity that arise from extrinsic or exogenous factors, such as electrical brain stimulation- or drug-induced neuroplasticity. The brain's ability to remodel itself forms the basis of the brain's capacity to retain memories, improve motor function, and enhance comprehension and speech amongst other things. It is this trait to retain and form memories that is associated with neural plasticity and therefore many of the functions individuals perform on a daily basis. This plasticity occurs as a result of changes in gene expression which are triggered by signaling cascades that are activated by various signaling molecules during increased neuronal activity.

<span class="mw-page-title-main">Nonsynaptic plasticity</span> Form of neuroplasticity

Nonsynaptic plasticity is a form of neuroplasticity that involves modification of ion channel function in the axon, dendrites, and cell body that results in specific changes in the integration of excitatory postsynaptic potentials and inhibitory postsynaptic potentials. Nonsynaptic plasticity is a modification of the intrinsic excitability of the neuron. It interacts with synaptic plasticity, but it is considered a separate entity from synaptic plasticity. Intrinsic modification of the electrical properties of neurons plays a role in many aspects of plasticity from homeostatic plasticity to learning and memory itself. Nonsynaptic plasticity affects synaptic integration, subthreshold propagation, spike generation, and other fundamental mechanisms of neurons at the cellular level. These individual neuronal alterations can result in changes in higher brain function, especially learning and memory. However, as an emerging field in neuroscience, much of the knowledge about nonsynaptic plasticity is uncertain and still requires further investigation to better define its role in brain function and behavior.

<span class="mw-page-title-main">Activity-regulated cytoskeleton-associated protein</span> Protein-coding gene in the species Homo sapiens

Activity-regulated cytoskeleton-associated protein is a plasticity protein that in humans is encoded by the ARC gene. The gene is believed to derive from a retrotransposon. The protein is found in the neurons of tetrapods and other animals where it can form virus-like capsids that transport RNA between neurons.

miR-132 Non-coding RNA molecule

In molecular biology miR-132 microRNA is a short non-coding RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms, generally reducing protein levels through the cleavage of mRNAs or the repression of their translation. Several targets for miR-132 have been described, including mediators of neurological development, synaptic transmission, inflammation and angiogenesis.

Memory allocation is a process that determines which specific synapses and neurons in a neural network will store a given memory. Although multiple neurons can receive a stimulus, only a subset of the neurons will induce the necessary plasticity for memory encoding. The selection of this subset of neurons is termed neuronal allocation. Similarly, multiple synapses can be activated by a given set of inputs, but specific mechanisms determine which synapses actually go on to encode the memory, and this process is referred to as synaptic allocation. Memory allocation was first discovered in the lateral amygdala by Sheena Josselyn and colleagues in Alcino J. Silva's laboratory.

While the cellular and molecular mechanisms of learning and memory have long been a central focus of neuroscience, it is only in recent years that attention has turned to the epigenetic mechanisms behind the dynamic changes in gene transcription responsible for memory formation and maintenance. Epigenetic gene regulation often involves the physical marking of DNA or associated proteins to cause or allow long-lasting changes in gene activity. Epigenetic mechanisms such as DNA methylation and histone modifications have been shown to play an important role in learning and memory.

Epigenetics of depression is the study of how epigenetics contribute to depression.

<span class="mw-page-title-main">Department of Neurobiology, Harvard Medical School</span> Academic Department at Harvard University Medical School, USA

The Department of Neurobiology at Harvard Medical School is located in the Longwood Medical Area of Boston, MA. The Department is part of the Basic Research Program at Harvard Medical School, with research pertaining to development of the nervous system, sensory neuroscience, neurophysiology, and behavior. The Department was founded by Stephen W. Kuffler in 1966, the first department dedicated to Neurobiology in the world. The mission of the Department is “to understand the workings of the brain through basic research and to use that knowledge to work toward preventive and therapeutic methods that alleviate neurological diseases”.

<span class="mw-page-title-main">Neuronal PAS domain protein 4</span> Protein-coding gene in the species Homo sapiens

Neuronal PAS domain protein 4 is a protein that in humans is encoded by the NPAS4 gene. The NPAS4 gene is a neuronal activity-dependent immediate early gene that has been identified as a transcription factor. The protein regulates the transcription of genes that control inhibitory synapse development, synaptic plasticity and most recently reported also behavior.

<span class="mw-page-title-main">Brenda Bloodgood</span> American neuroscientist

Brenda Bloodgood is an American neuroscientist and associate professor of neurobiology at the University of California, San Diego. Bloodgood studies the molecular and cellular basis of brain circuitry changes in response to an animal's interactions with the environment.

Lisa M. Monteggia is an American neuroscientist who is a Professor in the Department of Pharmacology, Psychiatry & Psychology as well as the Barlow Family Director of the Vanderbilt Brain Institute at Vanderbilt University in Nashville, Tennessee. Monteggia probes the molecular mechanisms underlying psychiatric disorders and has made critical discoveries about the role of the neurotrophins in antidepressant efficacy, the antidepressant mechanisms of Ketamine, as well as the epigenetic regulation of synaptic transmission by MeCP2.

Lauren Orefice is an American neuroscientist and assistant professor in the Department of Molecular Biology at Massachusetts General Hospital and in the Department of Genetics at Harvard Medical School. Orefice has made innovative discoveries about the role of peripheral nerves and sensory hypersensitivity in the development of Autism-like behaviors. Her research now focuses on exploring the basic biology of somatosensory neural circuits for both touch and gastrointestinal function in order to shed light on how peripheral sensation impacts brain development and susceptibility to diseases like Autism Spectrum Disorders.

References

  1. "Michael Greenberg". Archived from the original on 2013-05-12. Retrieved 2011-07-28.
  2. "Michael Greenberg, PhD - Children's Hospital Intellectual and Developmental Disabilities Research Center (IDDRC)". Archived from the original on 2011-07-26. Retrieved 2011-02-16.
  3. "Michael Greenberg | Harvard Catalyst Profiles | Harvard Catalyst".
  4. "Michael e. Greenberg | HarvardScience". Archived from the original on 2009-02-18. Retrieved 2009-04-12.
  5. "Greenberg Lab |". greenberg.hms.harvard.edu. Retrieved 2017-05-23.
  6. Dolmetsch, R. E.; Pajvani, U.; Fife, K.; Spotts, J. M.; Greenberg, M. E. (2001-10-12). "Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway". Science. 294 (5541): 333–339. Bibcode:2001Sci...294..333D. doi:10.1126/science.1063395. ISSN   0036-8075. PMID   11598293. S2CID   2768067.
  7. Takasu, Mari A.; Dalva, Matthew B.; Zigmond, Richard E.; Greenberg, Michael E. (2002-01-18). "Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors". Science. 295 (5554): 491–495. doi: 10.1126/science.1065983 . ISSN   1095-9203. PMID   11799243. S2CID   22063123.
  8. Kornhauser, Jon M.; Cowan, Christopher W.; Shaywitz, Adam J.; Dolmetsch, Ricardo E.; Griffith, Eric C.; Hu, Linda S.; Haddad, Chia; Xia, Zhengui; Greenberg, Michael E. (2002-04-11). "CREB transcriptional activity in neurons is regulated by multiple, calcium-specific phosphorylation events". Neuron. 34 (2): 221–233. doi: 10.1016/s0896-6273(02)00655-4 . ISSN   0896-6273. PMID   11970864. S2CID   14417223.
  9. Mardinly, AR; Spiegel, I; Patrizi, A; Centofante, E; Bazinet, JE; Tzeng, CP; Mandel-Brehm, C; Harmin, DA; Adesnik, H (2016-03-17). "Sensory experience regulates cortical inhibition by inducing IGF-1 in VIP neurons". Nature. 531 (7594): 371–375. Bibcode:2016Natur.531..371M. doi:10.1038/nature17187. ISSN   0028-0836. PMC   4823817 . PMID   26958833.
  10. Hong, Elizabeth J.; McCord, Alejandra E.; Greenberg, Michael E. (2008-11-26). "A Biological Function for the Neuronal Activity-Dependent Component of Bdnf Transcription in the Development of Cortical Inhibition". Neuron. 60 (4): 610–624. doi:10.1016/j.neuron.2008.09.024. ISSN   0896-6273. PMC   2873221 . PMID   19038219.
  11. Lin, Yingxi; Bloodgood, Brenda L.; Hauser, Jessica L.; Lapan, Ariya D.; Koon, Alex C.; Kim, Tae-Kyung; Hu, Linda S.; Malik, Athar N.; Greenberg, Michael E. (2008). "Activity-dependent regulation of inhibitory synapse development by Npas4". Nature. 455 (7217): 1198–1204. Bibcode:2008Natur.455.1198L. doi:10.1038/nature07319. PMC   2637532 . PMID   18815592.
  12. Kim, Tae-Kyung; Hemberg, Martin; Gray, Jesse M.; Costa, Allen M.; Bear, Daniel M.; Wu, Jing; Harmin, David A.; Laptewicz, Mike; Barbara-Haley, Kellie (2010). "Widespread transcription at neuronal activity-regulated enhancers". Nature. 465 (7295): 182–187. Bibcode:2010Natur.465..182K. doi:10.1038/nature09033. PMC   3020079 . PMID   20393465.
  13. Gabel, Harrison W.; Kinde, Benyam; Stroud, Hume; Gilbert, Caitlin S.; Harmin, David A.; Kastan, Nathaniel R.; Hemberg, Martin; Ebert, Daniel H.; Greenberg, Michael E. (2015). "Disruption of DNA-methylation-dependent long gene repression in Rett syndrome". Nature. 522 (7554): 89–93. Bibcode:2015Natur.522...89G. doi:10.1038/nature14319. PMC   4480648 . PMID   25762136.
  14. Ataman, Bulent; Boulting, Gabriella L.; Harmin, David A.; Yang, Marty G.; Baker-Salisbury, Mollie; Yap, Ee-Lynn; Malik, Athar N.; Mei, Kevin; Rubin, Alex A. (2016). "Evolution of Osteocrin as an activity-regulated factor in the primate brain". Nature. 539 (7628): 242–247. Bibcode:2016Natur.539..242A. doi:10.1038/nature20111. PMC   5499253 . PMID   27830782.
  15. "Biography Michael Greenberg - Rett Syndrome Research Trust". Archived from the original on 2009-11-09. Retrieved 2011-02-16.
  16. "Michael Greenberg | Harvard Catalyst Profiles | Harvard Catalyst".
  17. Michael E. Greenberg | HarvardScience
  18. The Brain Prize 2023