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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 explores molecular mechanisms that establish the diversity of neuronal phenotypes in brain. We are particularly interested in the mechanisms that regulate differentiation of neural stem cells in the post-natal and adult sub-ventricular zone. In rodent model systems, the production of neuronal progenitors from these neural stem cells peaks approximately a week after birth and continues throughout life. These progenitors migrate to the olfactory bulb and adopt one of the many different interneuron phenotypes. To investigate the mechanisms underlying adult neurogenesis in the adult sub-ventricular zone/olfactory bulb, our laboratory uses a wide array of molecular biological, biochemical andimmunohistochemical methods with both in vitro and in vivo paradigms. The goal of our research is to elucidate fundamental mechanisms regulating adult neurogenesis with a long-term aim of translating this knowledge into novel strategies to treat neurodengenerative disease or neurological injury.

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

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
The focus of the laboratory is to establish the mechanisms that regulate differentiation of neural stem cells (NSCs) in the adult subventricular zone (SVZ) of the lateral ventricles and to translate this knowledge into novel methods to treat neurological disease. In rodents, adult SVZ NSCs produce progenitors that normally migrate to the olfactory bulb and become interneurons. In humans, however, recent studies suggest that the adult SVZ NSCs produce progenitors that migrate to the striatum. Adult SVZ NSCs have several advantageous properties for therapeutic application when compared to either embryonic or induced pluripotent stem cells: (1) they are already committed to a neural lineage and do not require suppression of unwanted non-neural phenotypes; (2) they do not have the tumor-forming potential of either embryonic or induced pluripotent stem cells; and (3) they are 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. 

Differentiation of dopaminergic and GABAergic phenotypes
This project focuses on the mechanisms regulating transcription of the tyrosine hydroxylase (Th) and glutamic acid decarboxylase 1 (Gad1) genes, which encode the rate-limiting enzymes for biosynthesis dopamine and GABA neurotransmitters, respectively. Both enzymes are co-expressed in all dopaminergic interneurons of the olfactory bulb. The laboratory has identified several novel cis-regulatory regions that control transcription of these genes and we are establishing the specific transcription factors that bind to these regions. This work will provide an unprecedented molecular understanding in the specification of dopaminergic and GABAergic neurotransmitter phenotypes from SVZ NSCs.

Small molecule manipulation of neuronal gene expression
A novel discovery made by the laboratory while investigating dopaminergic differentiation is that the Th gene proximal promoter adopts G-quadruplex and i-motif DNA secondary structures. These structures repress gene transcription, and stabilization of these structures by small molecules (such as TMPyP4) facilitates transcriptional repression. A current objective is to define the roles that these secondary structures have in regulating transcription and translation of other neuronal genes in adult SVZ NSCs. We are also searching to identify novel chemical compounds that that selectively stabilize secondary structures in specific genes.

Specification of neuronal phenotypes by transcription factor expression
Adult SVZ NSCs are heterogeneous and produce different types of olfactory bulb interneurons. Many of these phenotypic subsets are defined by the expression of specific transcription factors. The goal of this project is to establish the molecular mechanisms by which these transcription factors specify distinct neuronal fates. We are particularly interested in the unique roles performed by the Er81 (Etv1), Pax6 and Foxp2 proteins. We seek to identify the target genes directly regulated by these transcription factors as well as understand how these transcription factors are differentially expressed in SVZ NSCs. We are also interested in understanding how the function of these transcription factors compare to the roles they also have in the development of other brains regions, such as the cortex and cerebellum. 

Adult neural stem cells as a source of replacement neurons for Parkinson’s Disease
Stem cells are an ideal source of neurons to make cell replacement therapy a practical treatment strategy for Parkinson’s Disease. A key challenge to effectively developing this therapeutic strategy is the efficient conversion of stem cells into clinically suitable neurons. Our laboratory is pursuing the use of adult SVZ NSCs as a source of replacement neurons. This project aims to define culture conditions that maximize the number of dopaminergic neurons progenitors generated from adult mouse SVZ NSCs. 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 NSCs can produce dopaminergic neurons suitable for cell replacement therapy to treat Parkinson’s Disease.   

Parkinson’s Disease in the human olfactory bulb
Nearly all cases of sporadic Parkinson’s Disease are associated with an impaired sense of smell many years before motor symptoms are detected. The cellular basis for this olfactory dysfunction, however, is not understood. This project examines post-mortem human olfactory bulb tissue from control and Parkinson’s Disease patients to establish whether specific neuronal populations in the olfactory bulb are vulnerable to Parkinson’s Disease-related degeneration. Identifying vulnerable populations in the olfactory bulb not only provides cellular mechanism for understanding olfactory dysfunction in Parkinson’s Disease, but also opens new routes to develop novel biomarkers that could greatly advance our ability to identify those at-risk of developing the disease. 

Laboratory

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
 





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

Former Members:

Ava Weibman
Parkinson Disease Foundation Summer Research Fellow
Oberlin College

Funding

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