Results Through Rehabilitation & Research
Assistant Professor, Neurology and Neuroscience
Weill Cornell Medical College
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.
University of California at Berkeley
Burke Medical Research Institute
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.
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.
Banerjee K, Akiba Y, Baker H, Cave JW (2013) Epigenetic control of neurotransmitter expression in olfactory bulb interneurons. Int J Dev Neurosci.(In press). 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. ProteinScience 9:2354-2365. PMID: 11206057
Differentiation of the olfactory bulb dopaminergic phenotype
This project focuses on the mechanisms regulating transcription of the tyrosine hydroxylase (Th) and glutamic acid decarboxylase1 (Gad1) genes, which encode the rate-limiting enzymes for biosynthesis dopamine and GABA neurotransmitters, respectively. Both of these enzymes are co-expressed in all dopaminergic interneurons of the olfactory bulb and our laboratory has identified several potentially novel cis-regulatory regions that control the transcription of these genes. We are presently testing the functionality of these novel regions as well as establishing the specific transcription factors that bind to them in order to define the mechanisms by which Th and Gad1 transcription is regulated. This work will provide an unprecedented molecular understanding in the specification of dopaminergic and GABAergic neurotransmitter phenotypes from neural stem cells in the sub-ventricular zone.
Regulation of adult neural stem cell proliferation and differentiation by microRNA
In collaboration with Tao Sun’s Laboratory (Weill Cornell Medical College), this project examines novel regulation of neural stem cell proliferation and differentiation by microRNA in the adult subventricular zone. These studies will establish both the specific target genes for these microRNA and whether these microRNA regulate the differentiation of a specific subset of olfactory bulb interneurons.
Specification of neuronal phenotypes by transcription factor expression
Neural stem cells within the adult subventricular zone are heterogeneous and produce different subsets of olfactory bulb interneuron phenotypes. 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 the expression of transcription factors are differentially controlled in subventricular zone neural stem cells. 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.
Human olfactory bulb
Studies in rodents indicate that throughout the entire life of the animal, olfactory bulb interneurons continuously turn over and are replaced by interneurons generated by the neural stem cells in the subventricular zone. In humans, however, the extent to which new interneurons generated in the subventricular zone integrate into the adult olfactory bulb is controversial. Our laboratory is interested in establishing whether the relative proportions of specific neuron phenotypes in the human olfactory bulb change throughout life and how specific olfactory bulb neuronal populations are affected by aging-related diseases, such as Parkinson’s Disease. Because nearly all cases of sporadic Parkinson’s Disease are associated with an impaired sense of smell many years before the motor symptoms are detected, we are particularly interested in establishing whether there is a select population of olfactory bulb neurons that are sensitive to Parkinson-mediated neurodegeneration. Such an identification would provide novel insight into the etiology of diseaseas well as open new routes to develop novel biomarkers that could greatly advance our ability to identify those at-risk of developing the disease.
M.D., Tianjin University
Ph.D., University of Louisville
Professor, Neurology Neuroscience
Burke Medical Research Institute
Parkinson Disease Foundation Summer Research Fellow
NIH R01 DC008955 (6/11-5/16) Plasticity in the Aging Olfactory System