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            [profile] => Array
                (
                    [id] => 1153410441
                    [firstname] => Mark
                    [lastname] => Zervas
                    [degrees] => B.S., M.S., Ph.D.
                    [title] => Assistant Professor of Biology
                    [department] => Molecular Biology, Cell Biology, & Biochemistry
                    [phone] => Tel:    401-863-6840
                    [phone2] => Fax:    401-863-9653
                    [email] => Mark_Zervas@brown.edu
                    [urls] => Array
                        (
                            [10] => Array
                                (
                                    [0] => Zervas Home Page
                                    [1] => http://research.brown.edu/myresearch/Mark_Zervas
                                )

                            [24] => Array
                                (
                                    [0] => Brown et al., 2009 (Video article describing GIFM)
                                    [1] => http://preview.ncbi.nlm.nih.gov/pubmed/20042997?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1
                                )

                            [25] => Array
                                (
                                    [0] => Ellisor et., 2009 (GIFM and neural circuits)
                                    [1] => http://preview.ncbi.nlm.nih.gov/pubmed/19616131?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=2
                                )

                            [26] => Array
                                (
                                    [0] => Joyner & Zervas, 2006 (GIFM Review)
                                    [1] => http://preview.ncbi.nlm.nih.gov/pubmed/16871622?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=10
                                )

                            [27] => Array
                                (
                                    [0] => Zervas et al., 2005 (Review of Neurodevelopment)
                                    [1] => http://preview.ncbi.nlm.nih.gov/pubmed/16243598?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=11
                                )

                            [28] => Array
                                (
                                    [0] => Zervas et al., 2005 (MAP1B and LTP)
                                    [1] => http://preview.ncbi.nlm.nih.gov/pubmed/16118800?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=12
                                )

                            [29] => Array
                                (
                                    [0] => Zervas et al., 2004 (Genetic Lineage, midbrain and dopamine neuron development)
                                    [1] => http://preview.ncbi.nlm.nih.gov/pubmed/15294143?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=13
                                )

                            [32] => Array
                                (
                                    [0] => Zervas et al., 2001 (ganglioside synthesis inhibition and Niemann-Pick Disease Type C)
                                    [1] => http://preview.ncbi.nlm.nih.gov/pubmed/11525744?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=17
                                )

                            [33] => Array
                                (
                                    [0] => Zervas et al., 2001 (Cellular pathology of NPC)
                                    [1] => http://preview.ncbi.nlm.nih.gov/pubmed/11202175?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=18
                                )

                            [34] => Array
                                (
                                    [0] => Zervas et al., 2000 (Ganlgiosides and cortical development and disease)
                                    [1] => http://preview.ncbi.nlm.nih.gov/pubmed/11007553?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=19
                                )

                            [35] => Array
                                (
                                    [0] => Zervas et al., 1999 (Gangliosides and cortical development)
                                    [1] => http://preview.ncbi.nlm.nih.gov/pubmed/10502250?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=21
                                )

                            [36] => Array
                                (
                                    [0] => Zervas et al., 1998 (Gangliosides and dendritic growth)
                                    [1] => http://preview.ncbi.nlm.nih.gov/pubmed/9668352?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=22
                                )

                            [37] => Array
                                (
                                    [0] => Zervas et al., 1996 (MAP1B mutant mice)
                                    [1] => http://preview.ncbi.nlm.nih.gov/pubmed/8577753?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=23
                                )

                            [38] => Array
                                (
                                    [0] => Ellisor & Zervas 2010 (Tamoxifen dose and GIFM)
                                    [1] => http://www.sciencedirect.com/science/article/pii/S1044743110001375
                                )

                            [39] => Array
                                (
                                    [0] => Luu et al., 2011 (Dynamic Gbx2 lineage contribution and requirement in spinal cord
                                    [1] => http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0020940
                                )

                            [40] => Array
                                (
                                    [0] => Brown et al., 2011 (Molecular identity of Wnt1-expressing progenitors and temporal contribution to dopamine neurons)
                                    [1] => http://onlinelibrary.wiley.com/doi/10.1002/cne.22710/abstract;jsessionid=456E3C12FC78C3229DB09B5916C9BFAF.d02t03
                                )

                        )

                    [images] => Array
                        (
                            [0] => Array
                                (
                                    [0] => 1156891251.jpg
                                    [1] => Genetic Inducible Fate Mapping demonstrates novel lineage boundary in vivo
                                )

                            [1] => Array
                                (
                                    [0] => 1156892110.jpg
                                    [1] => Genetic Inducible Fate Mapping showing Wnt1-derived cells during embryogenesis
                                )

                            [2] => Array
                                (
                                    [0] => 1156892518.jpg
                                    [1] => Wnt1 expression in mouse embryo (E8.5)
                                )

                            [4] => Array
                                (
                                    [0] => 1156893230.jpg
                                    [1] => midbrain dopaminergic neurons and their axonal projections
                                )

                            [5] => Array
                                (
                                    [0] => 1156893860.jpg
                                    [1] => Genetic Inducible Fate Mapping: The Wnt1 lineage (red) marked at E10.5 contributes to dopaminergic neurons (green) in vivo
                                )

                            [8] => Array
                                (
                                    [0] => 1156894912.jpg
                                    [1] => midbrain dopaminergic neuron circuitry schematic
                                )

                            [9] => Array
                                (
                                    [0] => 1157567214.jpg
                                    [1] => Purkinje and granule neurons of the cerebellum
                                )

                            [10] => Array
                                (
                                    [0] => 1158944120.jpg
                                    [1] => Genetic Inducible Fate Mapping (GIFM): Wnt1-CreER;R26R mouse embryo brain
                                )

                            [11] => Array
                                (
                                    [0] => 1244707712.jpg
                                    [1] => MRI of adult Wnt1 sw/sw (Swaying) mouse acquired at the Brown University MRI Research Facility (in collaboration with Ed Walsh & Mike Worden)
                                )

                            [12] => Array
                                (
                                    [0] => 1244707881.jpg
                                    [1] => MRI of adult Wnt1 sw/sw (Swaying) Brain acquired at the Brown University MRI Research Facility imaged at 3T using the Siemens AC88 gradient insert. Voxel size is 160 &#181;m^3 (in collaboration with Ed Walsh & Mike Worden)
                                )

                            [13] => Array
                                (
                                    [0] => 1244708119.jpg
                                    [1] => Genetic Inducible Fate Mapping Strategy
                                )

                            [14] => Array
                                (
                                    [0] => 1244708835.jpg
                                    [1] => Wnt1-derived midbrain dopamine neuron (green/red overlap) in a field of unmarked tyrosine hydroxylase expressing dopamine neurons (red)
                                )

                            [15] => Array
                                (
                                    [0] => 1244709012.jpg
                                    [1] => One of the lab interests: midbrain dopamine neurons
                                )

                            [16] => Array
                                (
                                    [0] => 1244709666.jpg
                                    [1] => 3D rendering of entire midbrain dopamine neuron population in adult mouse (top). Distribution of dopamine neurons expressing calbindin (green), calretinin (blue), GIRK2 (red).
                                )

                            [17] => Array
                                (
                                    [0] => 1244710247.jpg
                                    [1] => En1-Cre;Z/EG adult mouse brain (dorsal view). The cerebellum is derived from cells with a history of expressing En1 (green). The inset shows a mid-sagittal view of the cerebellum.
                                )

                            [20] => Array
                                (
                                    [0] => 1247273936.jpg
                                    [1] => Comparison of reporter alleles in E12.5 embryos (En1:Cre mediated recombination)
                                )

                            [21] => Array
                                (
                                    [0] => 1247274111.jpg
                                    [1] => Wnt1 derived trigeminal ganglia (Wnt1-CreER;Z/EG with tamoxifen administered at E8.5)
                                )

                            [22] => Array
                                (
                                    [0] => 1247274148.jpg
                                    [1] => Zervas Lab 2009
                                )

                            [23] => Array
                                (
                                    [0] => 1329449391.jpg
                                    [1] => Wnt1-derived calbindin-expressing dopamine neurons
                                )

                            [24] => Array
                                (
                                    [0] => 1329449554.jpg
                                    [1] => mouse ES cell derived dopamine neurons
                                )

                            [25] => Array
                                (
                                    [0] => 1329449894.jpg
                                    [1] => mouse ES cell derived calbindin-expressing dopamine neurons
                                )

                        )

                    [summary] => Dopamine neurons and the innervation of their targets mediate complex behaviors and their degeneration or aberrant function underpins Parkinson's disease and schizophrenia. My lab investigates how dopamine neuron circuits develop, how & when the loss of dopamine neurons of a distinct genetic lineage affects brain function, mechanisms of specifying/maintaining dopamine neurons and cell-based therapies to ameliorate deficits in genetically altered mice with features of neurological disorders.
                    [bio] => While studying pyramidal neurons differentiation and cortical development, I fortuitously showed that ectopic dendrite growth in metabolic brain disorders was accompanied by intra-neuronal cholesterol and ganglioside accumulation. I subsequently designed a therapeutic approach that ameliorated neuropathology in animal models of Niemann-Pick Disease Type C. This sparked my interest in brain development and disease and led to a clinical trial that resulted in therapy currently used to treat patients with NPC. <br />
<br />
My lab uses Genetic Inducible Fate Mapping (GIFM) to spatially and temporally mark small cohorts of cells and their progeny based on the expression of specific genes during embryogenesis. We then track these marked lineages to determine their behavior and contribution to brain regions, specific classes of neurons, and terminal neuronal fate generated during brain development. <br />
<br />
We have used this method to reveal that Wnt1-expressing progenitors are progressively restricted during midbrain development and that the Wnt1 lineage contributes to midbrain dopamine neurons in two distinct temporal peaks. In contrast, we show that the Wnt1 lineage originating in the cerebellum primordium at later stages contribute to the diverse array of cerebellum neurons. We have also elucidated the temporal contribution of Gbx2-expressing progenitors contribute to distinct cohorts of neurons in the developing and adult cerebellum, thalamus, and spinal cord.   <br />
<br />
We combine GIFM with conditional gene deletion to study the role of Tsc1/mTOR in thalamic neuron development and in establishing functional thalamocortical circuits. This approach has identified a novel subcortical node underlying neural and behavioral abnormalities associated with the developmental genetic disease, Tuberous Sclerosis. <br />
<br />
We also used GIFM and the conditional deletion of a novel conditional Wnt1 allele to uncover the dynamic temporal role of Wnt1 in midbrain dopamine neuron development. We are exploiting our knowledge of dopamine neuron development to instruct mouse embryonic stem cells to acquire a specific neuronal fate.
                    [interests] => <b>Overview of Research Interests</b> <br />
In the broadest sense I am interested in early developmental mechanisms that shape the brain and how these events can be exploited to understand neurological diseases.  <br />
<br />
A central problem in Developmental Neurobiology is how are relatively simple neuroepithelial tissues patterned and organized during embryogenesis to become highly organized anatomical and physiological structures like the brain?  An equally important problem in Neurological Disease is what are the aberrant genetic and cellular events that underpin distinct pathological features of brain disorders.  My lab uses sophisticated Genetic approaches in mouse to understand these seemingly unrelated disciplines implicit with the idea that unraveling and intervening in complicated disorders requires understanding how genetic identity is regulated during development, knowing the cell behaviors involved in brain morphogenesis, as well as having insight into how neurons of the brain are specified and the connections to their targets established.  In short, knowledge of developmental events may prove beneficial to understanding neurological diseases.<br />
<br />
<b>Background and Significance Underpinning my Research Interests</b><br />
Multiple types of neurons and neural circuits are coordinated to execute a complex array of tasks executed by the brain.  In particular, midbrain dopaminergic (MbDA) neurons of the substantia nigra pars compacta  (SNc) and ventral tegmental area (VTA) have axons that project over long distances to integrate spatially disparate regions into distinct functional units (circuits).  MbDA neuron circuits mediate motor behaviors and cognition and their degeneration or aberrant function has profound pathological consequences such as motor abnormalities accompanying Parkinson's disease or cognitive deficits associated with schizophrenia.  The loss of MbDA neurons of the SNc is a central feature of Parkinson's disease.  In contrast, the identification of a single substrate underpinning the pathophysiology of schizophrenia has remained elusive, although experimental and clinical pharmacology data strongly suggest that the dopamine system is also the fulcrum of schizophrenia.  Of particular interest are the MbDA neurons of the VTA, which innervate the dorsal lateral pre-frontal cortex (DLPFC) and ventral striatum.  VTA DA neurons are intricately involved in behaviors including motivation, reward, and cognition.  Deficiencies in VTA DA neurons appear to contribute to a broad array of cognitive disorders including schizophrenia.  These observations have led to a dopamine-centric hypothesis of schizophrenia that is often coupled with a supposition of developmentally dysregulated DA neuron circuitry.  However, such potential developmental defects have not been validated experimentally.  In addition, the genetic lineage and developmental mechanisms defining VTA and SNc DA neurons have not been determined.  Elucidating the mechanisms that link the genetic lineage of MbDA neuron sub-populations to precise circuit formation in vivo is essential to understand brain development and to gain insight into neurological disorders such as Parkinson's disease and schizophrenia.<br />
<br />
I previously used GIFM to show that Wnt1-derived progenitors give rise to MbDA neurons in vivo using Wnt1-CreER;R26R mice.  GIFM permanently and heritably marks small populations of progenitors and their descendants using  a modified Cre/loxP system and a conditional LacZ reporter allele encoding &#223;-galactosidase, which marks cell bodies.  In GIFM, precise temporal control of recombination (marking) is achieved by inducible Cre recombinase (CreER) while spatial control is obtained by region specific gene regulatory elements.  I established that cells expressing Wnt1 during embryogenesis give rise to different populations of Mb neurons in vivo.  Specifically, between embryonic day (E)8.5-11.5 the Wnt1-lineage contributes to MbDA, but not cholinergic, or serotonergic neurons.  However, how and when neurons of a distinct genetic lineage are organized into functional circuits in unknown.<br />
<br />
<b>Specific Aims to Test my Research Interests</b><br />
The central purpose of this my research interests is to understand how neurons derived from precursors expressing specific genes (genetic lineage) at distinct times are organized into functional circuits.  The central hypothesis of underpinning my research interests is that: Genetically-defined VTA and SN dopaminergic neurons project their axons to specific target sites at distinct time points to generate precisely organized functional circuits. The specific aims are:<br />
 <br />
<i><b>I.&#9;Determine when Wnt1-derived dopaminergic neurons establish VTA and SN circuitry in vivo.</b><br />
Hypothesis: The Wnt1 lineage at specific time points gives rise to VTA and SNc dopaminergic neurons that project to distinct targets. <br />
Experiments: Genetic Inducible Fate Mapping (GIFM) to establish a map of dopaminergic circuitry in vivo.</i><br />
<br />
<i><b>II.&#9;Establish how Mb dopaminergic neurons assemble into distinct nuclei in vivo.</b><br />
Hypothesis: Cohorts of genetically-related dopaminergic neurons are organized within distinct domains and this organization is reflected in their target field.  <br />
Experiment: Dual GIFM to uniquely mark cohorts of Wnt1-derived dopaminergic neurons as they form Mb nuclei and project to their target(s).</i><br />
<br />
<i><b>III.&#9;Ascertain how and when the loss of dopaminergic neurons of the Wnt1 lineage during development and in the adult impacts on dopamine circuitry in vivo.</b> <br />
Hypothesis: The loss of genetically-related VTA dopaminergic neurons in development versus the adult differentially affects the VTA dopaminergic circuitry.<br />
Experiments: Genetic ablation of Wnt1-derived dopaminergic neurons and analysis of targeted domains.</i> <br />
<br />
<i><b>IV.&#9;Determine the role of Wnt1 in specifying/maintaining Mb dopaminergic neurons in vivo.</b>  <br />
Hypothesis: Wnt1 specifies dopaminergic neuron phenotype and is required at specific time points.<br />
Experiments: GIFM on Swaying mutant background and conditional inactivation of Wnt1.</i><br />
<br />
<i><b>Future Directions of my research Interests</b><br />
*&#9;Hypothesis: Dopaminergic neuron degeneration can be rescued with cell-based strategies. <br />
Experiment: Stem cell transplantation of Wnt1-derived dopaminergic progenitors into Swaying mice.</i><br />
<br />
The above specific aims will determine how neurons of distinct lineages are specified, assembled into organized anatomical domains, and form functional units in vivo.  I will determine the functional significance of genetically defined circuits implicated by evaluating physiological and behavioral changes in mice with genetically ablated sub-populations of Wnt1-derived MbDA neurons, in mice with a genetic (point) mutation in Wnt1 (Swaying mice) and in Wnt1 conditional knockout mice. This type of comprehensive approach will be critical in understanding how to re-build these networks in a disease treatment context.  Toward this goal, I will evaluate the efficacy of cell-based therapies in regenerating depleted populations of MbDA neurons in Swaying mice as a model system.  First, I will evaluate whether Wnt1-derived neuronal precursors marked at specific time points can be isolated, expanded in vitro, and transplanted - with the goal of determining if they efficiently integrate into the ventral Mb of mice.  This will be done at developmental stages (determined in the above specific aims) and in the adult to ascertain when integration is most effective at repopulating depleted DA neurons.  Importantly, I will assess whether stem cell integration has led to meaningful temporal and spatial recapitulation of relevant MbDA neuron circuitry (determined in specific aims II and III) by virtue of the eGFP reporter allele as well as to an improvement in behavioral deficits.
                    [fresearch] => <b>Active Research Support</b><br />
2012-2015    DOD-CDMRP Idea Development Award (TS110083; $450,000)<br />
<b>Title:</b> Temporal loss of Tsc1: Neural development and brain disease in Tuberous Sclerosis.<br />
<b>Role:</b> Principle Investigator.<br />
<i> The major goals of this project are to identify critical windows of brain development that are affected by the loss of Tsc1 and mTOR dysregulation during embryonic development and to ascertain the impact of mTOR inhibitionon developing neurons during normal development and in Tuberous Sclerosis.</i><br />
<br />
2011-Present    COBRE Pilot Project sub-award; $12,500)<br />
<b>Title:</b> Determining the role of mTOR signaling in dopamine neuron cell fate decisions.<br />
<b>Role:</b> M. Zervas Sub-award Project leader (W. Atwood Principle Investigator, NIH 5-27961).<br />
<i> The major goal of this award is to develop stem cell based research projects designed to advance our understanding of programming embryonic stem cells and induced pluripotent stem cells. In addition, these funds are intended to foster a multi-disciplinary collaboration in stem cell biology (Brown Stem Cell Group).</i><br />
<br />
2011-2013    DOD-CDMRP Exploration Hypothesis Development Award (TS100067; $100,000)<br />
<b>Title:</b> Determining Changes in Neural Circuits in Tuberous Sclerosis.<br />
<b>Role:</b> Principle Investigator.<br />
<i> The major goals of this project are to conditionally delete Tsc1 in the thalamus during embryonic development and ascertain the impact on thalamocortical circuitry formation and on thalamic neuron physiology.</i><br />
<br />
2010-2013    NIH/NCRR RI Hospital COBRE Center for Stem Cell Biology<br />
Competitive Proposal Submission for Full Project (701-1960; $450,000)<br />
<b>Title:</b> Determining the Transcriptional Regulation and Cell Signaling Events that Shape the Molecular Identity of Dopamine Neuron Progenitors and Specify Subtypes of Midbrain Dopamine Neurons.<br />
<b>Role:</b> M. Zervas Project Leader (P. Quesenberry Principle Investigator, NIGMS 8P20GM103468-04)<br />
<i> The major goals of this project are to: 1. Elucidate the molecular identity of dopamine neuron progenitors; 2. Determine the genetic basis of dopamine neuron heterogeneity; 3. Investigate the role of WNT, SHH, and FGF8 signaling in establishing the molecular idenity cell and fate specification of dopamine neuron progenitors.</i><br />
<br />
2010-Present    Richard B. Salomon Faculty Research Award (2-34310; $15,000)<br />
<b>Title:</b> Genetic Dissection of Midbrain Dopamine Neuron Diversity.<br />
<b>Role:</b>  Principle Investigator<br />
<i> The goal of this project is to identify novel transcriptional regulators of dopamine neuron diversity using mouse genetic mutants, fluorescent activated cell sorting and microarray.</i>
                    [awards] => <b>2011</b> Invited to co-organize the Northeast Regional Meeting of the Society for Developmental Biology <br />
<br />
<b>2009</b> Tuberous Sclerosis Travel Award <br />
<br />
<b>2006-Present</b> Manning Assistant Professorship <br />
  <br />
<b>2003-2006</b> NIH Ruth L. Kirschstein National Research Service Award (F32HD43533)
                    [affiliations] => Member, Society for Developmental Biology<br />
Member, Society for Neuroscience
                    [teaching] => <b>Teaching</b><br />
Course Leader<br />
BIOL1310 and BIOL2310: Analysis of Development<br />
<br />
Course Leader<br />
BIOL2320A: Current Topics in Developmental Biology: Cell Fate and Lineage Decisions in Neural Development and Neurological Diseases<br />
<br />
<b>Mentoring</b> <br />
Four Brown University graduate students: two have graduated (Stephen Brown and Nellwyn Hagan) and two are in their final year.<br />
 <br />
One Brown University/NIH Graduate Partnership Program student (Lindsay Hayes), recently graduated.<br />
<br />
Thee Brown University undergraduate students (Brian Luu, Caroline Rieser, Juliana Guarente) who have completed their senior honors thesis work and a new student (Tina Voelcker)who just joined the lab.<br />
<br />
Instructor for CSHL Course on Stem Cells<br />
<br />
Lecturer & discussion leader for Boundaries and Compartments lecture, Foundations in Developmental Genetics Course, Skirball Graduate Curriculum<br />
<br />
Lecturer for Mouse Genetics lecture, Eukaryotic Genetics Course, Skirball Graduate Curriculum<br />
<br />
Mentor to 3 graduate students in three month-long rotations, Developmental Genetics Graduate Program<br />
 <br />
Mentor to undergraduate student in NYU/Sackler Institute Summer Undergraduate Research Program
                    [collab] => James (Yuanhao) Li, Ph.D. (Assistant Professor) 
Department of Genetics and Development Biology 
University of Connecticut Health Center
<b>contact:</b> jali@uchc.edu  

Sohyun Ahn, Ph.D. (Assistant Professor)
Unit on Developmental Neurogenetics/LMGD
NICHD/NIH 
<b>contact:</b> ahnsohyun@mail.nih.gov
<b>web link:</b> http://neuroscience.nih.gov/Lab.asp?Org_ID=120
                    [updated] => 1329450787
                    [date_created] => 1153410441
                    [primaryprogram] => BioMed: Molecular Biology, Cell Biology, and Biochemistry
                    [affiliatedprograms] => 1110482543
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                        )

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                    [affiliatedprogramlist] => BioMed: Neuroscience
                    [approved] => 1
                    [profile_url] => research.brown.edu/myresearch/Mark_Zervas
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<img height=32 src="/ttfs/drawstring_header.php?headertext=MARK ZERVAS" alt="MARK ZERVAS">  
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      Dopamine neurons and the innervation of their targets mediate complex behaviors and their degeneration or aberrant function underpins Parkinson's disease and schizophrenia. My lab investigates how dopamine neuron circuits develop, how & when the loss of dopamine neurons of a distinct genetic lineage affects brain function, mechanisms of specifying/maintaining dopamine neurons and cell-based therapies to ameliorate deficits in genetically altered mice with features of neurological disorders.      </p>
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	<p><strong>Overview</strong>&nbsp;&nbsp;|&nbsp;&nbsp;<a href="javascript:set_html('','/research/profile_myresearch.php?id=1153410441','researcher-pages');">Research</a>&nbsp;&nbsp;|&nbsp;&nbsp;<a href="javascript:set_html('','/research/profile_grants.php?id=1153410441','researcher-pages');">Grants/Awards</a>&nbsp;&nbsp;|&nbsp;&nbsp;<a href="javascript:set_html('','/research/profile_teaching.php?id=1153410441','researcher-pages');">Teaching</a>&nbsp;&nbsp;|&nbsp;&nbsp;<a href="javascript:set_html('','/research/profile_publications.php?id=1153410441','researcher-pages');">Publications</a></p><p><img src="/images/subhead/biography.gif" alt="Biography" width="225" height="16" style="padding-top:10px;"></p><p>While studying pyramidal neurons differentiation and cortical development, I fortuitously showed that ectopic dendrite growth in metabolic brain disorders was accompanied by intra-neuronal cholesterol and ganglioside accumulation. I subsequently designed a therapeutic approach that ameliorated neuropathology in animal models of Niemann-Pick Disease Type C. This sparked my interest in brain development and disease and led to a clinical trial that resulted in therapy currently used to treat patients with NPC. <br />
<br />
My lab uses Genetic Inducible Fate Mapping (GIFM) to spatially and temporally mark small cohorts of cells and their progeny based on the expression of specific genes during embryogenesis. We then track these marked lineages to determine their behavior and contribution to brain regions, specific classes of neurons, and terminal neuronal fate generated during brain development. <br />
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We have used this method to reveal that Wnt1-expressing progenitors are progressively restricted during midbrain development and that the Wnt1 lineage contributes to midbrain dopamine neurons in two distinct temporal peaks. In contrast, we show that the Wnt1 lineage originating in the cerebellum primordium at later stages contribute to the diverse array of cerebellum neurons. We have also elucidated the temporal contribution of Gbx2-expressing progenitors contribute to distinct cohorts of neurons in the developing and adult cerebellum, thalamus, and spinal cord.   <br />
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We combine GIFM with conditional gene deletion to study the role of Tsc1/mTOR in thalamic neuron development and in establishing functional thalamocortical circuits. This approach has identified a novel subcortical node underlying neural and behavioral abnormalities associated with the developmental genetic disease, Tuberous Sclerosis. <br />
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We also used GIFM and the conditional deletion of a novel conditional Wnt1 allele to uncover the dynamic temporal role of Wnt1 in midbrain dopamine neuron development. We are exploiting our knowledge of dopamine neuron development to instruct mouse embryonic stem cells to acquire a specific neuronal fate.</p><p><img src="/images/subhead/curriculumvitae.gif" alt="Curricum Vitae" width="225" height="16" style="padding-top:10px;"></p><p><a href="/pdf/1153410441.pdf?nocache=2131065287">Download Mark Zervas's Curriculum Vitae in PDF Format</a></p><p><img src="/images/fimages/1156891251.jpg"><br /><i>Genetic Inducible Fate Mapping demonstrates novel lineage boundary in vivo</i></p><p><img src="/images/fimages/1156892110.jpg"><br /><i>Genetic Inducible Fate Mapping showing Wnt1-derived cells during embryogenesis</i></p><p><img src="/images/fimages/1156892518.jpg"><br /><i>Wnt1 expression in mouse embryo (E8.5)</i></p><p><img src="/images/fimages/1156893230.jpg"><br /><i>midbrain dopaminergic neurons and their axonal projections</i></p><p><img src="/images/fimages/1156893860.jpg"><br /><i>Genetic Inducible Fate Mapping: The Wnt1 lineage (red) marked at E10.5 contributes to dopaminergic neurons (green) in vivo</i></p><p><img src="/images/fimages/1156894912.jpg"><br /><i>midbrain dopaminergic neuron circuitry schematic</i></p><p><img src="/images/fimages/1157567214.jpg"><br /><i>Purkinje and granule neurons of the cerebellum</i></p><p><img src="/images/fimages/1158944120.jpg"><br /><i>Genetic Inducible Fate Mapping (GIFM): Wnt1-CreER;R26R mouse embryo brain</i></p><p><img src="/images/fimages/1244707712.jpg"><br /><i>MRI of adult Wnt1 sw/sw (Swaying) mouse acquired at the Brown University MRI Research Facility (in collaboration with Ed Walsh & Mike Worden)</i></p><p><img src="/images/fimages/1244707881.jpg"><br /><i>MRI of adult Wnt1 sw/sw (Swaying) Brain acquired at the Brown University MRI Research Facility imaged at 3T using the Siemens AC88 gradient insert. Voxel size is 160 &#181;m^3 (in collaboration with Ed Walsh & Mike Worden)</i></p><p><img src="/images/fimages/1244708119.jpg"><br /><i>Genetic Inducible Fate Mapping Strategy</i></p><p><img src="/images/fimages/1244708835.jpg"><br /><i>Wnt1-derived midbrain dopamine neuron (green/red overlap) in a field of unmarked tyrosine hydroxylase expressing dopamine neurons (red)</i></p><p><img src="/images/fimages/1244709012.jpg"><br /><i>One of the lab interests: midbrain dopamine neurons</i></p><p><img src="/images/fimages/1244709666.jpg"><br /><i>3D rendering of entire midbrain dopamine neuron population in adult mouse (top). Distribution of dopamine neurons expressing calbindin (green), calretinin (blue), GIRK2 (red).</i></p><p><img src="/images/fimages/1244710247.jpg"><br /><i>En1-Cre;Z/EG adult mouse brain (dorsal view). The cerebellum is derived from cells with a history of expressing En1 (green). The inset shows a mid-sagittal view of the cerebellum.</i></p><p><img src="/images/fimages/1247273936.jpg"><br /><i>Comparison of reporter alleles in E12.5 embryos (En1:Cre mediated recombination)</i></p><p><img src="/images/fimages/1247274111.jpg"><br /><i>Wnt1 derived trigeminal ganglia (Wnt1-CreER;Z/EG with tamoxifen administered at E8.5)</i></p><p><img src="/images/fimages/1247274148.jpg"><br /><i>Zervas Lab 2009</i></p><p><img src="/images/fimages/1329449391.jpg"><br /><i>Wnt1-derived calbindin-expressing dopamine neurons</i></p><p><img src="/images/fimages/1329449554.jpg"><br /><i>mouse ES cell derived dopamine neurons</i></p><p><img src="/images/fimages/1329449894.jpg"><br /><i>mouse ES cell derived calbindin-expressing dopamine neurons</i></p></div>
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    <img src="/images/headshot/1153410441.jpg?nocache=1350718534"><p>MARK ZERVAS, B.S., M.S., Ph.D.<br />Assistant Professor of Biology<br />Molecular Biology, Cell Biology, & Biochemistry<br />Phone: Tel:    401-863-6840<br />Phone 2: Fax:    401-863-9653<br />E-mail: <a href="mailto:Mark_Zervas@brown.edu">Mark_Zervas@brown.edu</a></p>Mark Zervas's Brown Research URL:<br />
 	<strong>http://research.brown.edu/myresearch/Mark_Zervas</strong><br /><br />On The Web:<br /><a href="http://research.brown.edu/myresearch/Mark_Zervas" target="new">Zervas Home Page</a><br><a href="http://preview.ncbi.nlm.nih.gov/pubmed/20042997?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1" target="new">Brown et al., 2009 (Video article describing GIFM)</a><br><a href="http://preview.ncbi.nlm.nih.gov/pubmed/19616131?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=2" target="new">Ellisor et., 2009 (GIFM and neural circuits)</a><br><a href="http://preview.ncbi.nlm.nih.gov/pubmed/16871622?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=10" target="new">Joyner & Zervas, 2006 (GIFM Review)</a><br><a href="http://preview.ncbi.nlm.nih.gov/pubmed/16243598?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=11" target="new">Zervas et al., 2005 (Review of Neurodevelopment)</a><br><a href="http://preview.ncbi.nlm.nih.gov/pubmed/16118800?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=12" target="new">Zervas et al., 2005 (MAP1B and LTP)</a><br><a href="http://preview.ncbi.nlm.nih.gov/pubmed/15294143?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=13" target="new">Zervas et al., 2004 (Genetic Lineage, midbrain and dopamine neuron development)</a><br><a href="http://preview.ncbi.nlm.nih.gov/pubmed/11525744?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=17" target="new">Zervas et al., 2001 (ganglioside synthesis inhibition and Niemann-Pick Disease Type C)</a><br><a href="http://preview.ncbi.nlm.nih.gov/pubmed/11202175?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=18" target="new">Zervas et al., 2001 (Cellular pathology of NPC)</a><br><a href="http://preview.ncbi.nlm.nih.gov/pubmed/11007553?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=19" target="new">Zervas et al., 2000 (Ganlgiosides and cortical development and disease)</a><br><a href="http://preview.ncbi.nlm.nih.gov/pubmed/10502250?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=21" target="new">Zervas et al., 1999 (Gangliosides and cortical development)</a><br><a href="http://preview.ncbi.nlm.nih.gov/pubmed/9668352?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=22" target="new">Zervas et al., 1998 (Gangliosides and dendritic growth)</a><br><a href="http://preview.ncbi.nlm.nih.gov/pubmed/8577753?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=23" target="new">Zervas et al., 1996 (MAP1B mutant mice)</a><br><a href="http://www.sciencedirect.com/science/article/pii/S1044743110001375" target="new">Ellisor & Zervas 2010 (Tamoxifen dose and GIFM)</a><br><a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0020940" target="new">Luu et al., 2011 (Dynamic Gbx2 lineage contribution and requirement in spinal cord</a><br><a href="http://onlinelibrary.wiley.com/doi/10.1002/cne.22710/abstract;jsessionid=456E3C12FC78C3229DB09B5916C9BFAF.d02t03" target="new">Brown et al., 2011 (Molecular identity of Wnt1-expressing progenitors and temporal contribution to dopamine neurons)</a><br><p>Collaborators at other institutions:<br>James (Yuanhao) Li, Ph.D. (Assistant Professor) <br />
Department of Genetics and Development Biology <br />
University of Connecticut Health Center<br />
<b>contact:</b> jali@uchc.edu  <br />
<br />
Sohyun Ahn, Ph.D. (Assistant Professor)<br />
Unit on Developmental Neurogenetics/LMGD<br />
NICHD/NIH <br />
<b>contact:</b> ahnsohyun@mail.nih.gov<br />
<b>web link:</b> http://neuroscience.nih.gov/Lab.asp?Org_ID=120</p><p>Are you Mark Zervas? <a href="/faculty" target="blank">Click here</a> to edit your research profile.</p>	<p><a href="search.php">Back to search page</a></p>
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