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Neuroscience Graduate Program at UCSF

Faculty - John Rubenstein, M.D./Ph.D.

Genetic Regulation of Forebrain Development


Research Description

The embryonic neural tube differentiates into diverse structures depending upon their spatial coordinates within the embryo. The forebrain, which is at the rostral end of the neural tube, differentiates into the cerebral cortex, the basal ganglia and other components, each with distinct histologies and functions. Our laboratory is interested in studying the genes that regulate regional specification and differentiation of the mammalian forebrain particularly within the cerebral cortex and basal ganglia.

We are investigating the inductive mechanisms that pattern the neural plate and neural tube by analyzing the phenotypes of mice with mutations in genes encoding patterning molecules (e.g. SHH and FGF8) or encoding transcription factors that transduce patterning signals (e.g. Coup, Gsx, Nkx and Pax6).

To study neurogenesis, differentiation and migration within the forebrain we have been analyzing mouse mutants for several transcription factor genes that are expressed in the primordia of the basal ganglia (e.g. Dlx1, Lhx6, Npas1, and Zfhx1b) or cerebral cortex (e.g. COUP, Pbx1 and Tbr1). These studies are providing insights into the specification and differentiation of distinct types of neurons (Glutamatergic, GABAergic and Cholinergic). Within the basal ganglia, where GABAergic neurons are produced, subsets of these cells migrate tangentially to different destinations including the cerebral cortex. We are investigating the regulation of these tangential migrations and have evidence that neuropilin-semaphorin and cytokine signaling plays a key role in this process.

Finally, we are beginning to study the mechanisms that regulate the formation of circuitry within the forebrain. Our long-term aims are to understand the genetic underpinnings of forebrain evolution and function and to help elucidate mechanisms underlying human neurodevelopmental disorders.

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Current Projects

Role of transcription factors and signaling molecules (e.g. Dlx, Lhx, Nkx, Npas, Zfhx) in regulating specification, differentiation and tangential migration of forebrain GABAergic neurons.

Role of patterning centers expressing FGF, SHH, BMP, WNT and RA in regulating the expression of transcription factors (e.g. COUP, Nkx, Gsx, Pax6, Emx) that control regional specification of telencephalic subdivisions.

Identification of enhancer elements, and proteins that bind them, that regulate expression in developing forebrain.

Transplantation of interneurons to treat epilepsy.

Identification of genetic variants that contribute to autism susceptibility.

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Lab Members

Jasmine Chen, Postdoctoral Fellow
Pierre Flandin
, Postdoctoral Fellow
Olga Golonzhka, Postdoctoral Fellow
Renee Hoch, Postdoctoral Fellow
Jia Hu, Postdoctoral Fellow
Carol Kim, Research Associate
Susan Lindtner, Postdoctoral Fellow
Shyamali Mandal, Postdoctoral Fellow
Shanni Silberberg, Graduate Student
Kartik Pattabiraman Graduate Student
Ramon Pla, Postdoctoral Fellow
Magnus Sandberg, Postdoctoral Fellow 
Shanni Silberberg, Graduate Student
Daniel Vogt, Postdoctoral Fellow
Susan Yu, Administrative Assistant
Dongji Zhang, Research Associate

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Selected Publications

Link to Publications via PubMed

Rubenstein JLR, Martinez S, Shimamura K, Puelles L. (1994) Science 266, 578-560.
Shimamura K, Rubenstein JLR (1997) Inductive interactions direct early regionalization of the mouse forebrain. Develop 124, 2709-2718.

Anderson S, Eisenstat D, Shi L. and Rubenstein JLR (1997) Interneuron migration from basal forebrain:dependence on Dlx genes. Science 278, 474-476.

Miyashita-Lin, E, Hevner R, Montzka Wassarman K, Martinez, S, Rubenstein, J.L.R. (1999) Early neocortical regionalization is preserved in the absence of thalamic innervation. Science 285: 906-909.

Hevner R, Shi L, Justice N, Hsueh Y, Sheng M, Smiga S, Bulfone A, Goffinet A, Rubenstein, JLR (2001) Tbr1 regulates differentiation of the preplate & layer 6. Neuron 29. 353-366.

Marin O, Yarom A, Bagri A, Tessier-Lavigne M, Rubenstein JLR (2001) Semaphorin-Neuropilin interactions mediate sorting of striatal & cortical interneurons during development. Science 293, 872-875.

Depew MJ, Lufkin T, Rubenstein JLR (2002) Specification of jaw subdivisions by Dlx genes, Science 298:381-385.

Cobos I, Calcagnotto M, Vilaythong A, Noebels J, Baraban S, Rubenstein JLR (2005) Mice Lacking the Dlx1 Transcription Factor Exhibit Subtype-Specific Loss of Interneurons, Reduced Synaptic Inhibition & Epilepsy. Nature Neuro 8, 1059-1068.

Storm E, Garel S, Borello U, Hebert JM, Martinez S, McConnell S, Martin G and Rubenstein J. (2006) Dosage Dependent Functions of Fgf8 in Regulating Telencephalic Patterning Centers, Development. 133(9):1831-1844.

Sur M, Rubenstein,JLR. Patterning & plasticity of the cerebral cortex. (2005) Science 310:805-810.
Cholfin J and Rubenstein JLR (2007) Patterning of frontal cortex subdivisions by Fgf17. PNAS. 1;104(18):7652-7657.

Cobos I, Borello U, Rubenstein JLR. (2007) Dlx transcription factors promote migration through repression of axon and dendrite growth. Neuron. 54, 873–888.

Petryniak MA, Potter GB, Rowitch DH, Rubenstein JL. (2007) Dlx1 and Dlx2 Control Neuronal versus Oligodendroglial Cell Fate Acquisition in the Developing Forebrain. Neuron. 55(3):417-433.

Faedo A, Borello U, Rubenstein JL. (2010). Repression of fgf signaling by sprouty1-2 regulates cortical patterning in two distinct regions and times. J Neurosci. 30(11):4015-23.

Wang Y, Li G, Stanco A, Long JE, Crawford D, Potter GB, Pleasure SJ, Behrens T, Rubenstein JLR. (2011). CXCR4 and CXCR7 Have Distinct Functions in Regulating Interneuron Migration; Neuron 13;69(1):61-76.

Flandin, P., Zhou Y., Vogt V., Jeong J., Long J.E., Potter G.B., Westphal, H., Rubenstein J.L.R. 2011. Lhx6 and Lhx8 Coordinately Induce Neuronal Expression of Shh That Controls the Generation of Interneuron Progenitors. Neuron, 70(5):939-950.

McKinsey GL, Lindtner S, Trzcinski B, Visel A, Pennacchio L, Huylebroeck D, Higashi Y, and Rubenstein JLR. 2013. Dlx1&2-Dependent Expression of Zfhx1b (Sip1, Zeb2) Regulates the Fate Switch Between Cortical and Striatal Interneurons. Neuron, 77(1):83-98.

Visel A, Taher L, Girgis H, May D, Golonzhka O, Hoch R, McKinsey GL, Pattabiraman K, Silberberg SN, Blow MJ, Hansen DV, Nord AS, Akiyama JA, Holt A, Hosseini R, Phouanenavong S, Plajzer-Frick I, Shoukry M, Afzal V, Kaplan T Kriegstein AR, Rubin EM, Ovcharenko I, Pennacchio LA, Rubenstein JLR. (2013). A High-Resolution Enhancer Atlas of the Developing Telencephalon. Cell. 152(4):895-908.

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John Rubenstein, M.D./Ph.D.



Email

john.rubenstein@ucsf.edu

Phone

415-476-7862

Office Address

UCSF Mission Bay, Box 2611
Rock Hall, room 284C
1550 4th Street
San Francisco, CA 94158

Other Websites

Biomedical Sciences Graduate Program

Developmental & Stem Cell Biology Graduate Program

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research

Lab Website

PIBS Website

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