Rubenstein Lab – UCSF

Summary

Principal Investigator: John L. R. Rubenstein
UCSF Neuroscience

The goal of Rubenstein Lab research is to elucidate fundamental mechanisms that regulate development of the forebrain, with a focus on the cerebral cortex and basal ganglia. Our studies also extend into other regions of the embryo, including the developing face. Whenever possible, we attempt to investigate whether disruption of these mechanisms underlie human disorders, such as autism, schizophrenia, mental retardation, epilepsy and craniofacial disorders.

Principal Investigator: John L. R. Rubenstein
UCSF Neuroscience

The goal of Rubenstein Lab research is to elucidate fundamental mechanisms that regulate development of the forebrain, with a focus on the cerebral cortex and basal ganglia. Our studies also extend into other regions of the embryo, including the developing face. Whenever possible, we attempt to investigate whether disruption of these mechanisms underlie human disorders, such as autism, schizophrenia, mental retardation, epilepsy and craniofacial disorders.

 

Web Information

Website:  rubensteinlab.ucsf.edu/
BRAIN Initiative Grant – “Identification of enhancers whose activity defines cortical interneuron types”

Contact Information

Email: john.rubenstein@ucsf.edu
Phone: 415-476-7862
Address: John L.R. Rubenstein, M.D., Ph.D.
Genetics, Development and Behavioral Sciences Building
1550 4th Street, 2nd Floor South, Room GD 284C
University of California at San Francisco
San Francisco, CA 94143-2611

About the Lab

Mission
The goal of our research is to elucidate fundamental mechanisms that regulate development of the forebrain, with a focus on the cerebral cortex and basal ganglia. Our studies also extend into other regions of the embryo, including the developing face. Whenever possible, we attempt to investigate whether disruption of these mechanisms underlie human disorders, such as autism, schizophrenia, mental retardation, epilepsy and craniofacial disorders. We hope that our studies provide insights into new inroads for diagnosis, prevention and treatment of these disorders.

History
Our research group began at Stanford in 1988 to study genetic mechanisms of forebrain development. It was during this period that we discovered Dlx2 (Tes1). In 1991, the lab moved to UCSF, where it has remained. Shortly thereafter, the Nina Ireland Endowment created a new laboratory facility, first in Langley Porter Psychiatric Institute, and then in Rock Hall at the Mission Bay campus

Research

The embryonic neural tube differentiates into diverse structures depending upon their spatial coordinates. 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. In addition, we have a long-standing interest in integrating these findings to better understand the development and evolution of forebrain neural systems and to help elucidate mechanisms underlying human neurodevelopmental disorders such as Autism. Our laboratory has several types of projects.

Organization of the embryonic forebrain:

The discovery of regulatory genes with regionally restricted patterns of expression in the forebrain opened the door to the recognition of its embryonic subdivisions. With Luis Puelles, we investigate topological organization of distinct progenitor zones and their neuronal derivatives.

Forebrain patterning centers:

We investigate regions of the neural plate and neural tube that produce secreted factors that control regionalization and growth of the forebrain. Foremost in this arena have been our studies on Fgf8 and Fgf17 function in regionalization of the neural plate and cerebral cortex. This work has opened the door to elucidating the genetic circuitry of prefrontal cortex development, as Fgf17 mutant mice have hypoplasia of their anterior cingulate gyrus, and circumscribed behavioral deficits particularly in social interactions, providing insights into human neuropsychiatric disorders.

Transcription factors that control regional specification of brain subdivisions:

Ongoing studies focus on defining the transcription factors that control CNS development. These include the roles of the Nkx genes in specifying ventral neural progenitors (e.g. Nkx2.1 for globus pallidus principal neurons and cortical interneurons). These results are contributing towards elucidating the transcription factor code that defines the development programs of forebrain progenitor zones. This information shows linkage of regional and cell-type specification in the telencephalon; i.e. distinct telencephalic progenitor zones generally produce neurons that utilize different types of neurotransmitters. Ventral regions produce cholinergic, intermediate regions produce GABAergic and dorsal regions produce glutamatergic neurons.

Transcription factors that control and cell-type differentiation:

In this regard, we currently focus on the differentiation of forebrain GABAergic neurons, and the functions of the Dlx1, 2, 5 & 6, and Lhx6 & 8 transcription factors. Mutation of Dlx1&2 blocks differentiation of GABAergic neurons; see below.

Cortical inhibitory neurons are generated in the basal ganglia and tangentially migrate to the cortex:

There is migration of GABAergic neurons from the subcortical telencephalon into the cerebral cortex, where these cells become the major class of inhibitory neurons in the mouse. There is a similar tangential migration for cholinergic striatal interneurons. We are currently defining the molecular mechanisms that control the movement and integration of the migratory cells to their destinations.

Control of mature GABAergic cortical interneuron function:

Mutation of Dlx1 leads to an age-dependent death of a subset of dendrite innervating cortical interneurons. As these interneurons die, the mutant mice develop epilepsy. We are currently learning how Dlx function in neurons controls their function and survival. These insights could be pertinent for neuropsychiatric disorders, such as autism and schizophrenia, in which patients show largely normal development prior to the onset of symptoms. With Arturo Alvarez-Buylla, Scott Baraban and Arnold Kriegstein, we are developing methods for interneuron transplantation to treat forebrain disorders, such as epilepsies.

Neuropsychiatric Disorders (Autism):

The lab has a longstanding clinical interest in Autism. Ongoing studies involve sequencing of candidate genes, and functional analyses of mutant alleles.

Dlx Transcription factors that control craniofacial patterning:

Often neuropsychiatric disorders are associated with craniofacial dysmorphologies. Studies of Dlx function in craniofacial neural crest have illuminated the role of these genes in patterning the jaw and middle ear skeleton, findings that have important evolutionary and medical ramifications.

Publications

Books and Other Publications

Invited Reviews and Book Chapters

1988                Nicolas, J.F., and Rubenstein, J.L.R. Retroviral Vectors.  In: Vectors: a Survey of Molecular Cloning Vectors and Their Uses.  Rodriguez, R. and Denhardt, D.T. (eds)  Butterworth, 1988. (book chapter)

1990                Rubenstein, J.L.R., Lotspeich, L. and Ciaranello, R.D.  The neurobiology of developmental disorders. from: Advances in Clinical Child Psychology, vol 13, ed: B.B. Lahey and A.E. Kazdin.  Plenum Press. 1-52, 1990. (book chapter)

1990                Ciaranello, R.D., Wong, D.L. and Rubenstein, J.L.R.   Molecular neurobiology and disorders of brain development. from: Application of Basic Neuroscience to Child Psychiatry. ed:  S.I. Deutsch, A. Weizman, and R. Weizman.  Plenum Press. 9-32, 1990. (book chapter)

1994                Rubenstein, J.L.R. and Puelles, L. Homeobox gene expression during development of the vertebrate brain. Current Topics in Developmental Biology. ed. R. Pederson. Academic Press. 29, 1-64 .

1994                Rubenstein, J.L.R. Gene Cloning. from: Molecular Medicine. ed: E. Rubenstein. Scientific American Medicine, 103-132. Note: This book won the 1995 British Medical Association Medical Book of the Year Award and First Prize for the Best Basic and Clinical Sciences Book.

1988                        Rubenstein, J.L.R. (1998). Development of serotonergic neurons and their projections. Biol. Psych. 44, 145-150.

1998             Rubenstein, J.L.R.  (1998). Images in neuroscience. Brain development I. The neural plate.  American Journal of Psychiatry, 155(3):324.

1998                        Rubenstein J.L.R.  (1998) Development of the cerebral cortex: V. Transcription factors and brain development. Journal of the American Academy of Child and Adolescent Psychiatry, 37(5):561-562.

1999                Rubenstein, J.L.R. Overview of brain development. In: The Neurobiology of Mental Illness. D. Charney, E.J. Nestler, B.S. Bunney, Eds. Oxford University Press. New York, New York, Chapter 1.

1999                        Rubenstein, J.L.R. and Rakic, P. (1999). Genetic control of cortical development. Cerebral Cortex. 9: 521-523.

2000                Rubenstein, J.L.R. (2000) Intrinsic and Extrinsic Control of Cortical Development. Novartis Symposium 228: Evolutionary Developmental Biology of the Cerebral Cortex. Wiley, 67-74.

2000                        Parnavelas, J.G., Anderson, SA, Lavdas, AA, Grigoriou, M.. Pachnis V. and Rubenstein, J.L.R. (2000). The contribution of the ganglionic eminence to the neuronal cell types of the cerebral cortex. Novartis Symposium 228: Evolutionary Developmental Biology of the Cerebral Cortex. Wiley, 129-138.

2002             Puelles, L. and Rubenstein, J.L.R. (2002). Forebrain. Encyclopedia of the human brain. Academic Press, vol 2, 289-315.

2002                        Marin, O.  and Rubenstein, J.L.R. (2002). Patterning, regionalization and cell differentiation in the forebrain. In: Mouse Development, Editors: J. Rossant and P. Tam. Academic Press. 75-106.

2003                        Rubenstein, JLR and Puelles, L. (2003) Development of the Nervous System. For: Molecular Basis Of Inborn Errors of Development. Epstein CJ, Erikson RP and Wynshaw-Boris A, editors. Oxford University Press. Chapter 8.

2003                        Belmonte, MK, EH Cook, GM Anderson, JLR Rubenstein, WT Greenough,

A Beckel-Mitchener, E Courchesne, LM Boulanger, SB Powell, PR Levitt, EK Perry, Y Jiang, TM DeLorey, E Tierney. (2003). Autism as a Disorder of Neural Information Processing: Directions for Research and Targets for Therapy. Molecular Psychiatry. 9(7):646-663.

2004 Garel, S. and Rubenstein, JLR. (2004) Patterning of the Cerebral Cortex. The Cognitive Neurosciences, 3rd edition. Michael S. Gazzaniga Editor-in-Chief. MIT Press. November 2004.

2004                Puelles, L, Martínez S, and Rubenstein JLR. Gene maps and related histogenetic domains in the forebrain and midbrain. Chapter 1, The Rat Nervous System. Third Edition. Ed. Paxinos, Elsevier-Academic Press. pp. 3-25.

2004                Rubenstein, JLR and Puelles, L. (2004) Survey of Brain Development. Handbook of Mental Health Interventions in Children and Adolescents. Steiner, H, editor. Jossey-Bass Press. Chapter 5.

2006                        Understanding Autism: From Basic Neuroscience to Treatment (Book). Edited by Steven O. Moldin, John L. R. Rubenstein. CRC Press, 2006.

2006                        Moldin, SO, Rubenstein, JLR, Hyman, SE. (2006). Autism Speaks to Neuroscience. Commentary in: J. Neuroscience. 26(26):6893-6

2007                        Cholfin JA, Rubenstein JL. Genetic regulation of prefrontal cortex development and function.  Novartis Found Symp. 2007;288:165-73; discussion 173-7, 276-81.

2008                        Rubenstein, JLR and Puelles, L. (2008) Development of the Nervous System. Molecular Basis Of Inborn Errors of Development. Second Edition. Epstein CJ, Erikson RP and Wynshaw-Boris A, editors. Oxford University Press. Chapter 7.

2009                        Hoch, RV, Rubenstein JLR, Pleasure S. (2009). Genes and signaling events that establish regional patterning of the mammalian forebrain.  Seminars in Cell and Developmental Biology. 20(4):378-8

2010                        Rubenstein JL, (2010). Annual Research Review: Development of the cerebral cortex: implications for neurodevelopmental disorders. J Child Psychol Psychiatry. 2010. 52(4):339-55.

2011                        Tabarés-Seisdedos R, Dumont N, Baudot A, Valderas JM, Climent J, Valencia A, Crespo-Facorro B, Vieta E, Gómez-Beneyto M, Martínez S, Rubenstein JL. No paradox, no progress: inverse cancer comorbidity in people with other complex diseases. Lancet Oncol. 2011 Jun;12(6):604-8.

2011                        Messing RO, Rubenstein JL, Nestler E. (2011) Biology of Psychiatric Disorders, Harrisons Principles of Internal Medicine, 18th edition.  Eds: Dan L. Longo, Dennis L. Kasper, J. Larry Jameson, Anthony S. Fauci, Stephen L. Hauser, Joseph Loscalzo. Chapter 390. 2011.

2012                        Gelman DM, Marín O. Rubenstein JLR. (2012) The Generation of Cortical Interneurons. Section IV – Genetics” of Jasper’s Basic Mechanisms of the Epilepsies; Fr: Editors of Jasper’s Basic Mechanisms of the Epilepsies (J. Noebels, M. Avoli, M. Rogawski, R. Olsen, A.V. Delgado-Escueta). Oxford University Press.  786-796.

2013                Rubenstein JLR and Rakic P (editors in chief) (2013) Comprehensive Developmental Neuroscience. Academic Press, Three Volumes.

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