Pioneering Rehabilitation

John Cave, Ph.D.

Director, Laboratory for Neuronal Specification

Assistant Professor
Brain and Mind Research Institute
Weill Cornell Medicine


(914) 368-3140

Research Focus

Our laboratory studies mechanisms that regulate the proliferation and differentiation of adult neural stem cells, and the development of applications for this mechanistic knowledge to treat of neurological disease or injury.


A.B., Chemistry
Kenyon College

Ph.D., Chemistry
University of California at Berkeley

Post-doctoral fellowship
Burke Medical Research Institute

Burke Medical Research Institute
Weill Cornell Medical College, Brain Mind Research Institute

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.


Citations via PubMed

Fujiwara N, Cave JW (2016) Partial conservation between mice and humans in olfactory bulb interneuron transcription factor codes. Frontiers in Neuroscience 10:337. PMID: 27489533

Cave JW, Fujiwara N, Weibman A, Baker H (2016) Cytoarchitectural changes in the olfactory bulb of Parkinson’s Disease patients. npj Parkinson’s Disease 2: 16011.

Ding B, Cave JW, Mullikin-Kilpatrick D, Bartsokis M, Zhu H, Chow C-W, Gronostajski RM, Kilpatrick DL (2016) Mutually dependent auto-regulatory interactions between NFI occupancy and ETV1 drive the timing of dendrite-synapse gene programming in maturing cerebellar granule neurons. Molecular Biology of the Cell 27:1488-99. PMID: 26941328

Journal Edited by John W. Cave, Brett Langley and Rajiv R. Ratan (2016) Epigenetics and Disorders of the Nervous System Neuroscience Letter. 2016 June 20, Volume 625, Pages 1-80

John W. Cave, Brett Langley, Rajiv R. Ratan (2016) Nature and nurture meet at the epigenome to modulate disorders of the nervous system Neuroscience Letters. 2016 June 20, Volume 625, Pages 1-3

Dianna E. Willis, Meng Wang, Elizabeth Brown, Lilah Fones, John W. Cave (2016) Selective repression of gene expression in neuropathic pain by the neuron-restrictive silencing factor/repressor element-1 silencing transcription (NRSF/REST) Neuroscience Letters. 2016 June 20, Volume 625, Pages 20-25

Karuppagounder SS, Alim I, Khim SJ, Bourassa MW, Sleiman SF, John R, Thinnes CC, Yeh TL, Demetriades M, Neitemeier S, Cruz D, Gazaryan I, Killilea DW, Morgenstern L, Xi G, Keep RF, Schallert T, Tappero RV, Zhong J, Cho S, Maxfield FR, Holman TR, Culmsee C, Fong GH, Su Y, Ming GL, Song H, Cave JW, Schofield CJ, Colbourne F, Coppola G, Ratan RR (2016) Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models Sci Transl Med 2016 Mar;8(328):328ra29
PMID: 26936506

Wang M, Banerjee K, Baker H, Cave JW (2015) Nucleotide sequence conservation of novel and established cis-regulatory sites within the tyrosine hydroxylase gene promoter. Front Biol (Beijing). 2015 Feb 1;10(1):74-90.

Fujiwara N, Mazzola M, Cai E, Wang M, Cave JW (2015) TMPyP4, a Stabilizer of Nucleic Acid Secondary Structure, Is a Novel Acetylcholinesterase Inhibitor PLoS ONE 2015;10(9):e0139167
PMID: 26402367

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


Our laboratory studies mechanisms that regulate the proliferation and differentiation of adult neural stem cells, and the development of applications for this mechanistic knowledge to treat of neurological disease or injury. Much of our work is concentrated on molecular mechanisms that regulate gene expression.

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
  • Ÿmodifying expression levels of specific genes for therapeutic benefit, such as pain alleviation 

The studies in this project will 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. 

Unexpected connections between adult neural stem cells and reactive astrocytes

Astrocytes that act as neural stem cells in normal adult neurogenesis would seem to have little in common with reactive astrocytes generated by severe injury, but both types of astrocytes regulate cell adhesion gene expression in a manner similar to cellular epithelial-to-mesenchymal transitions in neural development and cancer. This project explores transcription regulatory mechanisms that control cell adhesion gene expression. These studies test the overall hypothesis that Zeb2 regulates cell adhesion gene expression in both adult neural stem cells and reactive astrocytes through a common molecular mechanism. Using both in vivo and in vitro systems, this project investigates whether Zeb2 regulates E- and N-Cadherin expression both in the production of neural progenitors within the adult subventricular zone neurogenic niche and the formation of reactive astrocytes in the brain following severe injury. The studies will also establish whether ZEB2 protein expression in both types of astrocytes is controlled by JAK-STAT pathway activation of Zeb2os, an opposite strand, long non-coding RNA transcript.

Phenotype specification and cellular organization in regenerating neural circuits

This project focuses on how phenotypes of neurons generated in the adult subventricular zone (SVZ) are specified and how these neurons integrate into mature olfactory 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 the olfactory 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 bulb provides an ideal system to study fundamental questions 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 organization 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.

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 properties for therapeutic application when compared to either embryonic or induced pluripotent stem cells. These include:

  • Ÿbeing 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 cells can produce dopaminergic neurons suitable for cell replacement therapy to treat Parkinson’s Disease.

Laboratory Members

Summer 2016

Current Lab Members

Lilah Fones
B.A. Wesleyan University


Former Lab Members:

Elizabeth Brown
B.S. University of Rochester

Meng Wang
Postdoctoral Fellow
M.D., Tianjin University
Ph.D., University of Louisville

Bryan Chatterton
Undergraduate Summer Student
University of Connecticut

Katie Konopka
Undergraduate Summer Student
University of Rochester

Natcha Rummaneethorn
Undergraduate Summer Student
Manhattanville College

Nana Fujiwara
Cornell University

Elizabeth Cai
Princeton University

Michael Mazzola
Undergraduate Summer Student
Hunter R. Rawlings III Cornell Presidential Research Scholar
Cornell University

Ava Weibman
Undergraduate Summer Student
Parkinson Disease Foundation Summer Research Fellow
Oberlin College


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