Graybiel Laboratory Department of Brain and Cognitive Sciences
McGovern Institute for Brain Research
Research Publications In The News Contact Us Links    

Jill Crittenden

Email Jill

 

I am interested in how molecular signaling cascades impact our control of motor behavior. Our ability to initiate specific actions and simultaneously inhibit inappropriate motor movements is dependent on signaling through the basal ganglia, a group of brain nuclei that integrate and focus cortical information. Cortical input to the basal ganglia is via the striatum, a large subcortical structure that receives excitatory inputs from all areas of the cortex. The striatum is enriched in various neurochemicals, such as dopamine, acetylcholine, opioids and endocannabinoids, that signal through cell-surface receptors to modulate cortical inputs and control motor behaviors. Such neuromodulation is thought to enhance our ability to learn specific sequences of motor behaviors that lead to reward. However, disruption of signaling through basal ganglia nuclei can have both motoric and psychological consequences. For example, degeneration of the dopaminergic system, as occurs in Parkinson’s disease, leads to a loss of voluntary movement and increased risk of depression. By contrast, drugs of abuse stimulate parts of the striatum and elevate both mood and motor behaviors. In Huntington’s disease, loss of medium spiny neurons in the striatum is correlated with uncontrollable motor movements and mood disturbances.

To understand molecular mechanisms underlying the control of motor behaviors, I have focused on studies of signaling molecules that are enriched in the striatum. My studies are part of a collaboration between the laboratories of Profs. Ann Graybiel and David Housman, thus providing a multi-disciplinary approach, ranging from molecular biology to neuroanatomy and behavioral analyses, to understanding motor control. We have focused on two families of signaling molecules, termed CalDAG-GEFs (aka RasGRPs) and cAMP-GEFs (aka EPACs). By generating and studying mice that lack these signaling proteins, we have discovered how these proteins contribute to normal biological functions. We are particularly focused on how these molecules are changed in post-mortem samples from individuals with movement disorders, and whether manipulation of these signaling molecules can ameliorate symptoms in models of Huntington’s disease, drug addiction, repetitive movement disorders such as autism and OCD, and dyskinesias associated with Parkinson’s disease therapy.

We have discovered that CalDAG-GEFI (calcium- and diacylglycerol-regulated guanine nucleotide exchange factor I) is required for calcium-dependent adhesion in platelets, a hematopoietic cell type that normally serves to arrest bleeding following an injury. This discovery led to the development of a genetic test for CalDAG-GEFI mutations, which are now known to cause bleeding disorders in dogs, cattle and horses. Whether CalDAG-GEFI mutations are associated with diseases in humans remains unknown. We have, however, found that CalDAG-GEFI expression levels are low in post-mortem striatal tissue from individuals with Huntington’s disease and in mouse models of Huntington’s disease. Most importantly, down-regulation of CalDAG-GEFI in a rat brain slice model of Huntington’s disease is neuroprotective. Based on these results, we hypothesize that the down-regulation of CalDAG-GEFI in Huntington’s disease is a compensatory mechanism to protect against neurotoxicity caused by mutant Huntingtin protein. This could be related to the fact that CalDAG-GEFI is specifically enriched in the medium spiny neurons of the striatum and that this neuronal subtype undergoes preferential degeneration in Huntington’s disease. As is observed in most diseases caused by expansions of nucleotide triplets (ie CAG), the expression of the disease-causing allele is wide-spread but neurodegeneration is somehow restricted to a subset of neuronal cell types. Thus, down-regulation of genes that are enriched in these vulnerable cell types might be beneficial to resisting neurotoxic effects of the disease-causing mutation.

Aberrant signaling in medium spiny neurons of the striatum contributes to another serious movement disorder, termed L-DOPA-induced dyskinesia. L-DOPA-induced dyskinesias are severe and unwanted motor movements that occur in response to L-DOPA therapy for Parkinson’s disease. To identify molecular changes that might contribute to this disorder, we measured gene expression in striatal neurons from a rat model of L-DOPA-induced dyskinesia, relative to controls that were treated only with L-DOPA or only with dopamine-depleting neurotoxins. We discovered that striking changes occurred in the expression of CalDAG-GEFs in the rats that developed dyskinesia: CalDAG-GEFI was down-regulated whereas CalDAG-GEFII was up-regulated, at both the mRNA and protein levels. This observation is interesting in regards to CalDAG-GEFI function, because it represents a second motor disorder (in addition to Huntington’s disease), in which there is a correlation between excessive movement and low CalDAG-GEFI. The possibility that loss of CalDAG-GEFI contributes to hyperkinesia is supported by our studies of mice lacking CalDAG-GEFI, which exhibit exaggerated motoric responses to psychomotor stimulants. This hyper-responsivity phenotype fits with reports that CalDAG-GEFI transduces signaling from acetylcholine receptors in cultured cells. In PC12D cells, the M1 muscarinic acetylcholine receptor stimulates the ERK MAP kinase pathway via CalDAG-GEFI activation. Data from numerous laboratories implicate the M1 muscarinic receptor and the ERK MAP kinases in motor control and responses to indirect dopamine receptor agonists such as L-DOPA and psychomotor stimulants. The cholinergic system is in a delicate balance with the dopaminergic system to control movement and both of these systems are exploited for therapeutic benefit in movement disorders. Nevertheless, the need for more targeted therapies remains, owing to serious side-effects associated with current medications. We are therefore testing if manipulation of CalDAG-GEFI or CalDAG-GEFII expression levels may provide some relief of symptoms in mouse models of L-DOPA-induced dyskinesias and also how these gene manipulations impact compulsive and pathologically repetitive behaviors.

The finding that CalDAG-GEFI and CalDAG-GEFII are oppositely dysregulated in models of L-DOPA-induced dyskinesia is intriguing for its potential consequences on compartmentalized striatal signaling. The dorsal striatum is comprised of two distinct compartments, termed striosomes (or patch) and matrix. CalDAG-GEFI and CalDAG-GEFII are oppositely enriched in these two compartments: CalDAG-GEFI expression is primarily in medium spiny neurons of the matrix whereas CalDAG-GEFII is more highly expressed in striosomal medium spiny neurons. The striosome/matrix categorization of striatal neurons is distinct from the direct/indirect pathway classification, and is much less well understood. In the classic but surely over-simplified view of striatal circuitry, the direct pathway projects to the internal globus pallidus and the substantia nigra pars reticulata, which are the output nuclei of the basal ganglia that control movement through their projections to brainstem motor nuclei and, via the thalamus, to the primary motor cortex. The indirect pathway projects first to the external globus pallidus and subthalamic nucleus before finally reaching the basal ganglia output nuclei. A balance of activity between these two pathways is thought to activate specific motor movements and simultaneously inhibit competing ones. Both striosomes and matrix contain striatal neurons that target the direct and indirect pathway nuclei, however, the matrix makes up most of the dorsal striatum and thus contains the majority of the direct and indirect pathway neurons. The striosomes are intermingled throughout the matrix and contain a special class of striatal neurons that project to the dopamine-containing neurons of the substantia nigra pars compacta. Furthermore, in brain slice studies, the striosome and matrix compartments have been found to exert differential presynaptic control of dopamine release. Thus, the striosomes are in a position to modulate striatal signaling by both local and global effects on dopamine release. An imbalance in striosome versus matrix activity has been associated with several movement disorders, including L-DOPA-induced dyskinesias, Huntington's disease, dystonia and drug addiction. These diseases share features of abnormally repetitive behaviors and mood disturbances. Some of this compartmentalized signaling imbalance may be related to disease-related dysregulation of the CalDAG-GEFs and other compartmentally-enriched molecules. We are working to identify genes that are dysregulated in these movement disorders and whether selective modulation of striosome or matrix compartment signaling can ameliorate symptoms in animal models. 

 

BUSINESS ADDRESS
McGovern Institute for Brain Research and Center for Cancer Research
Massachusetts Institute of Technology
46-6133
77 Massachusetts Ave.
Cambridge, MA 02139
TEL: (617)253-3010
FAX: (617)253-5202

EDUCATION

1993-1998 Baylor College of Medicine, Houston, TX
Ph.D. Dept. of Cell Biology

Thesis with Ronald L. Davis: Neuroanatomical dissection of Drosophila mushroom bodies, and the identification of D-mef2 as critical to their formation

1991-1993 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
Graduate research with Carol W. Greider

1988-1991 Indiana University, Bloomington, IN
B.S. Microbiology Undergraduate research with Miriam E. Zolan

RESEARCH EXPERIENCE

2005-current Massachusetts Institute of Technology, Cambridge, MA
Research Scientist with Ann M. Graybiel and David E.Housman
Development and characterization of mouse models of movement disorders, with an emphasis on basal ganglia signaling.

2000-2005 Massachusetts Institute of Technology, Cambridge, MA
Postdoctoral Fellow with Ann M. Graybiel and David E.Housman

1998-2000 Baylor College of Medicine
Postdoctoral Associate with Ronald L. Davis

TEACHING EXPERIENCE

1991 Instructor for Introductory Biology Laboratory with Carl Moos, SUNY Stony Brook, NY
1991 Assistantship for Introductory Genetics with Peter Gergen, SUNY Stony Brook, NY



SUPERVISORY EXPERIENCE (MIT Undergraduate Research Program)

Urvashi Upadhyay
Sudeb Dalai
Catherine Smith
Lara Hershcovitch
Mariam Shaikh
Jin Suk Calvin Kim
Seema Verma
Tao Liu
George Zhengliang Li
Lulu Wang
Zachary Nash
Judy Deng
Soraya Shehata


AWARDS AND FELLOWSHIPS

2010 Travel Award for the 10th Internation Basal Ganglia Society Meeting
2009 Osaka University Global Center of Excellence Travel Award
2008-2010 Michael J Fox Foundation for Parkinsonís Research, Target Validation Grant, Co-PI
2006 Outstanding MIT Undergraduate Research Mentorship Award
2005-2010 Simons Grant for Autism Research, Key Personnel
2002-2005 Postdoctoral NIMH F32 Research Fellowship
1993-1996 Predoctoral NIMH F31 Research Fellowship
1991-1992 Predoctoral NIH T32 Research Fellowship SUNY Stony Brook
1990-1991 Undergraduate Howard Hughes Medical Initiative Award
1990 Undergraduate Honors Research Award (Indiana University)

INVITED TALKS

Captive animals' stereotypic behaviours: Signs of brain sysfunction, poor welfare, or both?
Biotechnology and Biological Sciences Research Council International Workshop, Lanzarote, Spain, Sept. 13-20, 2010.

Striatal dysregulation of CalDAG-GEFI and CalDAG-GEFII in movement disorders.
Massachusetts General Hospital Movement Disorders Seminar Series, Boston, MA, Nov. 12, 2009.

CalDAG-GEFI modulates motor behaviors and neuropathology in models of movement disorders.
Osaka University, Osaka, Japan, Sept. 4, 2009.

CalDAG-GEFI modulates behavioral sensitization to psychomotor stimulants and is required for cortico-striatal long-term potentiation.
University of Connecticut Behavioral Neuroscience Seminar Series, Storrs, CT, April 3, 2008.

Toward a molecular basis of repetitive behaviors.
Tufts University Neuroscience Seminar Series, Boston, MA, March 5, 2008.

The striatum-enriched signaling molecule, CalDAG-GEF1, modulates behavioral responses to amphetamine and cocaine.
Stanley Center Seminar Series at the Broad Institute, MIT. Cambridge, MA, Oct. 24, 2007.

The striatal signaling molecules CalDAG-GEF1 and CalDAG-GEF2 modulate repetitive and locomotor behaviors induced by psychostimulants.
NIMH Workshop on Translational Approaches to Studying Repetitive Behavior and Resistance to Change in Autism, Washington, D.C., Sept. 7, 2007.

AD HOC MANUSCRIPT REVIEWS

Neurobiology of Disease
Neurobiology of Aging
Neuropsychopharmacology
Journal of Neurodevelopmental Disorders

PATENT APPLICATION

Crittenden, J.R., Housman, D.E. and Graybiel. A.M. The use of protein inhibitors as antithrombotic agents. Filed June 2, 2003.


PUBLICATIONS

Crittenden, J. R., Sauvage, M., Burguierem E. Yim, M. J., Cepeda, C., Andre, V., Costa, C., Martella, G., Liu, T., Verma, S., Harlan, P., Levine, M., Calabresi, P., Housman, D. E., and Graybiel, A. M. Caldag-GEFI modulates behavioral sensitization to psycho-motor stimulants and is required for cortico-striatal long-term potentiation. (In preparation)

Crittenden, J. R. and Graybiel, A. M. Basal ganglia disorders associated with imbalances in the striatal striosome and matrix compartments. Frontiers in Neuroanatomy, 5:59 (2011).

Cantuti-Castelvetri I, Hernandez LF, Keller-McGandy CE, Kett LR, Landy A, Hollingsworth ZR, Saka E, Crittenden J. R., Nillni EA, Young AB, Standaert DG, Graybiel AM. Levodopa-induced dyskinesia is associated with increased thyrotropin releasing hormone in the dorsal striatum of hemi-parkinsonian rats. PLoS One. 5(11): e13861 (2010).

Crittenden J. R., Dunn DE, Merali FI, Woodman B, Yim M, Borkowska AE, Frosch MP, Bates GP, Housman DE, Lo DC, Graybiel AM. (2010) CalDAG-GEFI down-regulation in the striatum as a neuroprotective change in Huntington's disease. Hum Mol Genet. 19(9): 1756-65 (2010).

Crittenden, J. R., Cantuti-Castelvetri, I., Saka, E., Keller-McGandy, C., Fernandez-Hernandez, L., Kett, L. R., Young, A. B., Standaert, D. G., and Graybiel, A. M. Dysregulation CalDAG-GEFI and CalDAG-GEFII predicts the severity of motor side-effects induced by anti-Parkinsonian therapy. Proc Natl Acad Sci USA 106, 2892-6 (2009).

Pasvolsky R., Feigelson S. W., Kilic S. S., Simon A. J., Tal-Lapidot G., Grabovsky V., Crittenden, J. R., Amariglio N., Safran M., Graybiel A. M., Rechavi G., Ben-Dor S., Etzioni A., and Alon R. A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets. J Exp Med 204, 1571-82 (2007).

Bergmeier W., Goerge T., Wang H. W., Crittenden J. R., Baldwin A. C., Cifuni S. M., Housman D. E., Graybiel A. M., and Wagner D. D. Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III. J Clin Invest 117, 1699-707 (2007).

Crittenden, J. R., Heidersbach, A. and McManus, M. T. Lentiviral strategies for RNAi knockdown of neuronal genes. Current Protocols in Neuroscience (2007).

Bernadi, B., Guidetti, G. F., Campus, F. Crittenden, J. R., Graybiel, A. M., Balduini, C. and Torti. M. The small GTPase Rap1b regulates the cross-talk between platelet integrin a2b1 and integrin aIIbb3. Blood 107, 2728-2735 (2006).

Crittenden, J. R., Bergmeier*, W., Zhang, Y., Piffath, C. L., Liang, Y., Wagner, D. D., Housman, D. E. and Graybiel, A. M. CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Nature Medicine 10, 982-986 (2004).

Crittenden, J. R. RNA Modalities in Huntingtonís Disease Therapy, HDF Workshop Report (2002).

Crittenden, J. R., Skoulakis, E. M. C., Han, K. A., Kalderon, D. and Davis, R. L. Tripartite mushroom body architecture revealed by antigenic markers. Learning and Memory 5, 38-51 (1998).

Harrington, L. A., Hull, C. M., Crittenden, J. R. and Greider, C. W. Gel shift and UV cross-linking analysis of Tetrahymena telomerase. J Biol Chem 270, 8893-8901 (1995).

Zolan, M. E., Crittenden, J. R., Heyler, N. K. and Seitz, L. C. Efficient isolation and mapping of rad genes of the fungus Coprinus cinereus using chromosome-specific libraries. Nucleic Acids Research 20, 3993-3999 (1992).



SCIENTIFIC CONFERENCE POSTER PRESENTATIONS

Crittenden, J. R., Sauvage, M., Burguiere, E., Yim, M. J., Costa,C., Martella, G., Ghiglieri, V., Zhang, H., Pescatore, K. A., Liu, T., Unterwald, E. M., Picconi, B., Sulzer, D., Calabresi P. and Graybiel, A. M. CalDAG-GEFI is required for normal striatum-based egocentric maze learning in mice and the balance between cholinergic and dopaminergic signaling in the striatum. Society for Neuroscience Annual Meeting, San Diego, CA 2010.

Crittenden J. R., Dunn D. E., Merali F. I., Woodman B., Yim M., Borkowska A. E., Frosch M. P., Bates G. P., Housman D. E., Lo D. C., and Graybiel A. M. CalDAG-GEFI down-regulation in the striatum as a neuroprotective change in Huntington's disease. The Hereditary Disease Foundation Milton Wexler Celebration Meeting, Cambridge, MA 2010.

Crittenden J. R., Yim, M. J., Fischer, K. B. and Graybiel, A. M. Sensitization and tolerance to amphetamine-induced behaviors in mice are differentially maintained during withdrawal. International Basal Ganglia Society X meeting, Long Branch, NJ 2010.

Crittenden, J. R., Dunn, D., Borkowska, A., Woodman, B., Merali, F. I., Frosch, M., Housman, D. E., Bates, G. P., Lo, D. C. and Graybiel, A. M. Down-regulation of CalDAG-GEFI is neuroprotective in a Huntington disease model. Society for Neuroscience Annual Meeting, Chicago, IL 2009.

Crittenden, J. R., Fernandez-Hernandez, L., Yim, M. J., Keller-McGandy, C., Cantuti-Castelvetri, I., Standaert, D. G., and Graybiel, A. M. Evaluation of the striatum-enriched genes, CalDAG-GEFI and CalDAG-GEFII, for the treatment and prevention of L-DOPA-induced dyskinesias. Michael J. Fox Foundation Parkinson’s Disease Therapeutic Conference, New York, NY 2009.

Crittenden, J. R., Dunn, D., Merali, F. I., Woodman, B., Bates, G. P., Housman, D. E., Lo, D. C. and Graybiel, A. M. Down-regulation of the striatum-enriched signaling molecule, CalDAG-GEF1/RasGRP2, is protective in a model of mutant Htt-induced neurodegeneration. The Hereditary Disease Foundation Milton Wexler Celebration Meeting, Cambridge, MA 2008.

Crittenden, J. R., Sauvage, M., Cepeda, C., Andre, V., Costa, C., Martella, G., Liu, T., Verma, S., Levine, M., Calabresi, P., Housman D.E., and Graybiel, A. M. CalDAG-GEFI modulates behavioral sensitization to psychomotor stimulants and is required for cortico-striatal long-term potentiation. The American College of Neuropsychopharmacology Annual Meeting, Boca Raton, FL 2007.

Crittenden, J. R., Cantuti-Castelvetri, I., Saka, E., Fernandez-Hernandez, L., Keller-McGandy, C., Harlan, P., Kett, L. R., Housman, D. E., Standaert, D. G., Young, A. B., and Graybiel, A. M. The striatal signaling molecule, CalDAG-GEF2, is up-regulated in the dopamine-depleted striatum of hemi-parkinsonian rats. Society for Neuroscience Annual Meeting, San Diego, CA 2007.

Crittenden, J. R., Picconi, B., Ghiglieri, V., Calabresi, P., Harlan, P., Housman D. E., and Graybiel A. M. CalDAG-GEFI is required for sensitization to amphetamine-induced stereotypy and cortico-striatal LTP, but not for locomotor sensitization and LTD. Society for Neuroscience Annual Meeting, Washington, D.C. 2006.

Crittenden, J. R., Sauvage, M., Picconi, B., Costa, C., Martella, M., Andre, V., Cepeda, C., Levine, M., Calabresi, P. Housman D. E., and Graybiel, A. M. The striatum-enriched signaling molecule, CalDAG-GEFI, is essential for cortico-striatal LTP and sensitization of drug-induced stereotypies. Cellular and Molecular Treatments of Neurological Diseases Meeting, Cambridge, MA 2006.

Crittenden, J. R., Sauvage, M., Picconi, B., Costa, C., Martella, M., Andre, V., Cepeda, C., Levine, M., Calabresi, P. Housman D. E., and Graybiel, A. M. The striatum-enriched signaling molecule, CalDAG-GEFI, is essential for cortico-striatal LTP and sensitization of drug-induced stereotypies. The Hereditary Disease Foundation HD (CAG)n Meeting, Cambridge, MA 2006.

Crittenden, J. R., C. Costa, G., Martella, G., Calabresi, P., Harlan, P., Sauvage, M., Housman D. E., and Graybiel, A. M. CalDAG-GEFI is critical for striatal plasticity. Society for Neuroscience Annual Meeting, Washington, D.C. 2005.

Crittenden, J. R., Bergmeier, W., Zhang, Y., Liang, Y., Wagner, D. D., Housman, D. E. and Graybiel, A. M. Calcium and diacylglycerol signal through CalDAG-GEFI to control platelet aggregation. Gordon Research Conference, Newport, RI, 2004.

Crittenden, J. R. and Davis, R.L. The role of D-mef2 in developing mushroom bodies. 40th Annual Drosophila Research Conference, Bellvue, WA, 1999.