Professor of Neurobiology*
*Coates Family Professor of Neuroscience, Helen Wills Neuroscience Institute; Director, QB3 Functional Genomics Laboratory
Our lab is interested in understanding the molecular and cellular mechanisms underlying the function, development and regeneration of the vertebrate olfactory system. We use a wide range of experimental tools and model systems, including molecular biology, genomics, computational biology and behavior to study these processes using the mouse and zebrafish as model systems. We are also developing genomics and genome engineering technologies to characterize the neuronal diversity in the cerebral cortex and other regions of the nervous system.
Olfactory Stem Cells and Neural Regeneration. In the vertebrate olfactory system, primary sensory neurons are continuously regenerated throughout adult life via the proliferation and differentiation of multipotent neural progenitor cells. This feature makes the olfactory system particularly amenable for studies on adult neurogenesis and the properties of neuronal stem cells. Olfactory sensory neurons normally turn over every 30-60 days and are replaced through the proliferation and differentiation of multipotent progenitor cells. Following injury that results in the destruction of mature cells in the olfactory epithelium, these adult tissue stem cells proliferate and differentiate to reconstitute all cellular constituents of this sensory epithelium. The regenerative capacity of the olfactory epithelium represents a powerful and experimentally accessible paradigm for understanding the regulation of neural stem cell function under normal conditions and during injury-induced regeneration. While distinct stages of the olfactory lineage have been identified, however, much remains to be learned about the genetic programs that both define and regulate olfactory neurogenesis during development and regeneration. Current projects are using a variety of approaches – including targeted gene knockouts to assess the function of transcription factors and stem cell factors, and single cell RNA sequencing – to elucidate the molecular and cellular mechanisms regulating olfactory stem cells and olfactory neurogenesis in the mouse.
Olfactory Behavior. An understanding of the neural circuits underlying innate behaviors is required for an eventual understanding of the causes of human conditions such as chronic fear and anxiety. Many innate behaviors begin with the reception of a sensory stimulus and subsequent processing of diverse and complex inputs by the brain. In the olfactory system, pheromones can excite specific receptors in select neurons to cause a fixed action response. We are using the zebrafish as an experimental model for elucidating the networks driving sensory guided innate behaviors. Compared to mammalian species, zebrafish have a relatively simple and therefore experimentally tractable nervous system, and their fear behavior can be controlled by a small molecule alarm pheromone. This alarm pheromone causes an innate fear response mediated by the olfactory system. The alarm response shows many of the hallmarks of mammalian fear behaviors, and the behavior of adult and larval zebrafish to alarm pheromone is similar to a fear response generated by other sensory inputs. Moreover, zebrafish are amenable to genetic and chemical manipulation, and their embryos are transparent, which enables concurrent imaging and optogenetic control of neuronal network activity and assaying for fear behavior.
The Ngai Lab BRAIN Initiative Project: Classification of Cortical Neurons by Single Cell Transcriptomics. A major goal of neuroscience is to understand how circuits of neurons and non-neuronal cells process sensory information, generate movement, and subserve memory, emotion and cognition. Elucidating the properties of neural circuits requires an understanding of the cell types that comprise these circuits and their roles in processing and integrating information. However, since the description of diverse neuronal cell types over a century ago by Ramon y Cajal, we have barely scratched the surface of understanding the diversity of cell types in the brain and how each individual cell type contributes to nervous system function. Current approaches for classifying neurons rely upon features including the differential expression of small numbers of genes, cell morphology, anatomical location, physiology, and connectivity – important descriptive properties that nonetheless are insufficient to fully describe or predict the vast number of different cell types that comprise the mammalian brain. This NIH-supported BRAIN Initiative project – a collaboration between the Ngai lab and 9 other research groups at UC Berkeley – aims to provide a suite of technologies for identifying and classifying the diverse cell types in the mammalian nervous system.
Brunet, L.J., G.H. Gold, and J. Ngai. 1996. General anosmia caused by a targeted disruption of the mouse olfactory cyclic nucleotide-gated cation channel. Neuron 17, 681-693. PMID: 8893025
Barth, A.L., J.C. Dugas, and J. Ngai. 1997. Noncoordinate expression of odorant receptor genes tightly linked in the zebrafish genome. Neuron 19, 359-369. PMID: 9292725
Lin, D.M., F. Wang, G. Lowe, G. H. Gold, R. Axel, J. Ngai, and L. Brunet. 2000. Formation of precise synaptic connections in the olfactory bulb occurs in the absence of odorant-evoked neuronal activity. Neuron 26, 69-80. PMID: 10798393
Diaz, E., Y. Ge, Y.H. Yang, K.C. Loh, T. Serafini, Y. Okazaki, Y. Hayashizaki, T.P. Speed, J. Ngai, and P. Scheiffele. 2002. Molecular analysis of gene expression in the developing pontocerebellar projection system. Neuron 36, 417-434. PMID: 12408845
Duggan, C.D., S. DeMaria, A. Baudhuin, D. Stafford, and J. Ngai. 2008. Foxg1 is required for development of the vertebrate olfactory system. J. Neurosci. 28, 5229-5239. PMID: 18480279 PMCID: PMC2706027
Scolnick, J.A., K. Cui, S. Xuan, C.D. Duggan, X.-b Yuan, A. Efstratiadis, and J. Ngai. 2008. Role of IGF signaling in olfactory sensory map formation and axon guidance. Neuron 57, 847-857. PMID: 18367086 PMCID: PMC2364597
Cancer Genome Atlas Research Network. 2008. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061-1068. PMID: 18772890 PMCID: PMC2671642
Triballeau, N., E. Van Name, G. Laslier, D. Cai, G. Paillard, P.W. Sorensen, R. Hoffman, H.O. Bertrand, J. Ngai, and F.C. Acher. 2008. High potency olfactory receptor agonists discovered by virtual high-throughput screening: molecular probes for receptor structure and olfactory function. Neuron 60, 767-774. PMID: 19081373 PMCID: PMC2652502
Cameron, P., M. Hiroi, J. Ngai, and K. Scott. 2010. The molecular basis for water taste in Drosophila. Nature 465, 91-96. PMID: 20364123 (Free PMC Article)
Fletcher, R.B., M.S. Prasol, J. Estrada, A. Baudhuin, K. Vranizan, Y.G. Choi, and J. Ngai. 2011. p63 regulates olfactory stem cell self-renewal and differentiation. Neuron 72, 748-759. PMID: 22153372 PMCID: PMC3240811
DeMaria, S., A. Berke, E. Van Name, A. Heravian, T. Ferreira and J. Ngai. 2013. Role of a ubiquitously expressed receptor in the vertebrate olfactory system. J. Neurosci. 33, 15,235-15,247. PMID: 24048853 PMCID: PMC3776066
Ferreira, T., S.R. Wilson, Y.G. Choi, D. Risso, S. Dudoit, T.P. Speed and J. Ngai. 2014. Silencing of odorant receptor genes by G protein bg signaling ensures the expression of one odorant receptor per olfactory sensory neuron. Neuron 81, 847-859. PMID: 24559675
Last Updated 2015-01-27