Faculty

Pioneering Rehabilitation

John Cave, Ph.D.

Director, Laboratory for Neuronal Specification

Assistant Professor, Neurology and Neuroscience

Weill Cornell Medical College

Phone:

(914) 368-3140

Research Focus

Our laboratory is interested in mechanisms that generate and maintain neuronal identity. Much of our work is concentrated on molecular mechanisms that regulate gene expression. The long-term goal of the laboratory is to establish collaborations that enable translation of this basic mechanistic information into novel treatments for neurological disease.

Biography

A.B., Chemistry
Kenyon College

Ph.D., Chemistry
University of California at Berkeley

Post-doctoral fellowship
Burke Medical Research Institute

Instructor
Burke Medical Research Institute
Weill Cornell Medical College, Department of Neurology and Neuroscience

John graduated from Kenyon College with a degree in Chemistry. Under the supervision of Dr. David Wemmer, he earned a doctoral degree in Chemistry studying protein structure and dynamics by solution nuclear magnetic resonance at the University of California at Berkeley. Several of the proteins he studied during his graduate training were gene transcription regulatory factors, which spurred an interest in the developmental role played by these proteins. Pursuing this interest, John joined the Burke Medical Research Institute as a post-doctoral fellow to investigate gene transcription regulatory mechanisms mediated by the Notch signaling pathway that are necessary for neural precursor cell development in Drosophila melanogaster. In 2006, he became an Instructor at the Burke Medical Research Institute and Weill Cornell Medical College Department of Neurology and Neuroscience. John collaborated with Dr. Harriet Baker to study specification of the dopaminergic neuronal phenotype in the mammalian olfactory bulb. In 2012, John was promoted to Assistant Professor at the Burke Medical Research Institute and Weill Cornell Medical College Department of Neurology and Neuroscience. His laboratory is interested in elucidating the molecular mechanisms that establish the diversity of neuronal phenotypes in brain. The laboratory is currently focused on the regulation of neural stem cell differentiation in the post-natal and adult subventricular zone.

Publications

Wang M, Banerjee K, Baker H, Cave JW (2015) Identification of novel nucleotide sequence conservation within the tyrosine hydroxylase gene promoter. Front Biol 10:74-90. PMID:25774193.

Banerjee K*, Wang M*, Cai E, Fujiwara N, Baker H, Cave JW (2014) Regulation of tyrosine hydroxylase transcription by hnRNP K and DNA secondary structureNature Commun 5:5769. PMID 25493445

Cave JW, Baker H (In press) Adult Neurogenesis in the SVZ and Migration to the Olfactory Bulb. In Handbook of Olfaction and Gustation. R Doty (Ed). New York, NY: Marcel Dekker.

Cave JW, Wang M, Baker H (2014) Adult subventricular zone neural stem cells as a potential source of dopaminergic replacement neurons. Front Neurosci 8:16. PMID: 24574954

Banerjee K, Akiba Y, Baker H, Cave JW (2013) Epigenetic control of neurotransmitter expression in olfactory bulb interneurons. Int J Dev Neurosci 31:415-423. PMID: 23220178

Cave JW, Banerjee K, Baker H (2012) Species-specific molecular mechanisms establishing the dopamine neuronal phenotype. In Dopamine: Functions, Regulation and Health Effects. E Kudo & Y Fujii (Eds).Happauge, NY: Nova Science Publishers. 

Cave JW (2011) Selective repression of Notch pathway target gene transcription. Dev Biol 1:123-31.

Cave JW, Li X, Caudy MA (2011) Differential transcriptional regulation through distinct suppressor of hairless DNA binding site architectures in proneural clusters during notch signaling. Mol Cell Biol 31:22-9. PMID: 21041480

Cave JW, Akiba Y, Banerjee K, Berlin RA, Baker H (2010) Differential regulation ofdopaminergic gene expression by Er81. J Neurosci 30:4717-24. PMID: 20357122

Akiba Y, Cave JW, Akiba N, Langley B, Ratan RR, Baker H (2010) Histone deacetylase activity represses tyrosine hydroxylase expression in olfactory bulb interneuron progenitors. Biochem Biophys Res Comm 393:673-7. PMID: 20170631 

Cave JW, Baker H (2009) Dopamine systems in the forebrain. Adv Exp Med Biol 651:15-35. PMID: 19731547

Cave JW, Li X, Caudy MA (2009) The daughterless N-terminus directly mediates synergistic interactions with notch transcription complexes via the SPS+A DNA transcription code. BMC Res Notes 2:65. PMID: 19400956

Akiba N, Jo S, Akiba Y, Baker H, Cave JW (2009) Expression of EGR-1 in a subset of olfactory bulb dopaminergic cells. J Mol Histology 40:151-5. PMID: 19387849 

Akiba Y, Saski H, Baker H, Estevez A, Cave JW (2009) GABA-mediated regulation of the activity-dependent olfactory bulb dopaminergic phenotype. J Neurosci Res 87:2211-21. PMID: 19301430

Cave JW, Caudy MA (2008) Promoter-specific co-activation by mastermind. Biochem Biophys Res Comm 377:658-661. PMID: 18930034

Saino-Saito S, Cave JW, Akiba Y, Sasaki H, Goto K, Kobayashi K, Berlin RA, Baker H (2007) ER81 and CaMKIV identify anatomically and phenotypically defined subsets of olfactory bulb interneurons. J Comp Neurol 502:485-496. PMID: 17394138 

Cave JW, Loh F, Surpris JW, Xia L, Caudy MA (2005) A DNA transcription code for cell-specific gene activation by notch signaling. Current Biology 15:94-104. PMID: 15668164

Cave JW, Cho HS, Batchelder AM, Yokota H, Kim R, Wemmer DE (2001) Solution nuclear magneticresonance structure of a protein disulfide oxidoreductase from methanococcus jannaschii. Protein Science 10:384-396. PMID: 11266624 

Cave JW, Kremer W, Wemmer DE (2001) Backbone dynamics of sequence specific recognition and binding by the yeast Pho4 bHLH domain probed by NMR. Protein Science 9:2354-2365. PMID: 11206057

Current Projects

Overview

Our laboratory is interested in mechanisms that generate and maintain neuronal identity. Much of our work is concentrated on molecular mechanisms that regulate gene expression. The long-term goal of the laboratory is to establish collaborations that enable translation of this basic mechanistic information into novel treatments for neurological disease.

Phenotype specification andcellular organization in regenerating neural circuits

This project focuses onhow phenotypes of neurons generated in the adult subventricular zone (SVZ) are specified and how these neurons integrate into matureolfactory bulb circuits. The olfactory bulb is the initial processing center for odorant sensory information, and mitral and tufted projection neurons within the bulb relay odorant information from olfactory receptor neurons in the olfactory epithelium to cortical regions, such as the piriform cortex. This relay is modulated by interneurons in the olfactory bulb. Whereas mitral and tufted projection neurons are generated during embryonic development, most of theolfactory bulb interneuron population is generated by progenitors produced in the post-natal SVZ. In adult rodents, olfactory bulb interneuronsturn over and are regenerated by progenitors produced by neural stem cells in the SVZ. The olfactory bulb interneuron population is not homogenous, however, and there are several distinct interneuron sub-types based on the co-expressed of other neurotransmitters, neuroactive peptides and calcium binding proteins. Olfactory bulb interneurons also make different synaptic connections depending on the layer in which they reside. Thus, the SVZ and olfactory bulbprovides an ideal system to study fundamentalquestions about gene transcription regulatory mechanisms that direct phenotype specification and circuit organization.

Our laboratory is currently interested in understanding how the GABAergic phenotype that is expressed by nearly all olfactory bulb interneurons is specified. We are also investigating how specific sub-types of olfactory bulb GABAergic interneurons are specified, such as those that also co-express dopamine. Furthermore, the laboratory is addressing how laminar organizationin the interneuron population is established. For example, how are migrating adult-born progenitors directed to either the glomerular or granule cells layers? Finally, the laboratory is also interested in understanding how disease or injury alters these specification and organizing mechanisms.

 

Small molecule manipulation of gene expression

Nucleic acid secondary structures, such as G-quadruplexes and i-motifs, are emerging as important regulators of gene expression in the nervous system. Our laboratory has recently shown that nucleic acid secondary structures are instrumental in regulating the expression of tyrosine hyrdoxylase and glutamic acid decarboxylase 1. This research project builds on these recent findings and explores the potential of using small molecules to modulate nucleic acid secondary structure stability in order to manipulate gene expression in either mature neurons or neural progenitors. There are several directions that we are pursuing with this strategy, including:

  • Ÿproviding neuroprotection from oxidative stress resulting from either stroke or neurodegeneration
  • altering cell fate in differentiating neural progenitors
  • Ÿ modifying expression levels of specific genes for therapeutic benefit, such as pain alleviation 

The studies in this projectwill provide new and fundamental insights into the role that nucleic acid secondary structure has in regulating gene expression in the nervous system. Furthermore, these studies will address whether nucleic acid secondary structures are effective molecular targets for treating neurological diseases that offer exciting opportunities for developing novel pharmacological therapies.

 

Adult neural stem cells as a source of replacement neurons for Parkinson’s Disease

Stem cells are an ideal source of neuronsto make cell replacement therapy a practical treatment strategy for Parkinson’s Disease.Adult SVZ neural stem cells have several advantageous propertiesfor therapeutic application when compared to either embryonic or induced pluripotent stem cells. These include:

  • Ÿ being already committed to a neural lineage
  • not having the tumor-forming potential of either embryonic or induced pluripotent stem cellsŸ
  •  being a potential source of autologous replacement neurons since they can be endoscopically harvested from the lateral ventricle wall by penetrating non-eloquent parts of the brain

This project aims to define culture conditions that maximize the number of dopaminergic neurons progenitors generated from adult mouse SVZ neural stem cells.A second aim is to demonstrate that dopaminergic neurons can be efficiently generated from human adult SVZ NSCs and that these dopaminergic progenitors can provide functional relief in a PD rodent model system.Together, these studies will establish whether adult SVZ neural stem cellscan produce dopaminergic neurons suitable for cell replacement therapy to treat Parkinson’s Disease.

 

 

 

 

Laboratory


Summer 2014


Current Members:
 

Meng Wang 

Postdoctoral Fellow
M.D., Tianjin University
Ph.D., University of Louisville
mew3001@med.cornell.edu 
 



Elizabeth Cai

Technician
A.B., Princeton University
elc3004@med.cornell.edu




Nana Fujiwara 

Technician
B.S., Cornell University
 




Katie Konopka
Undergraduate
University of Rochester

Harriet Baker, Ph.D.
Professor, Neurology Neuroscience
Burke Medical Research Institute 

Former Members:

Michael Mazzola
Burke Summer Science Research Scholar
Hunter R. Rawlings III Cornell Presidential Research Scholar
Cornell University 

Ava Weibman
Parkinson Disease Foundation Summer Research Fellow
Oberlin College

Funding

NIH R01 DC008955 (6/11-5/16) Plasticity in the Aging Olfactory System