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 Niemann-Pick Disease Type C.
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.
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.
We use GIFM and the conditional deletion of a novel conditional Wnt1 allele we generated 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.
We also 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 a complex developmental genetic disease, Tuberous Sclerosis.
Active Research Support
2014-2017 DOD-CDMRP Idea Development Award
Title: Timing of mosaic gene deletion in mouse blastocysts and multi-tissue disease development in Tuberous Sclerosis.
Role: Principal Investigator.
2013-2015 Simons Foundation Autism Research Initiative
Title: Linking genetic mosaicism, neural circuit abnormalities and behavior.
Role: Principal Investigator.
2012-2015 DOD-CDMRP Idea Development Award (TS110083; $450,000)
Title: Temporal loss of Tsc1: Neural development and brain disease in Tuberous Sclerosis.
Role: Principal Investigator.
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.
2011-Present COBRE Pilot Project sub-award; $12,500)
Title: Determining the role of mTOR signaling in dopamine neuron cell fate decisions.
Role: M. Zervas Sub-award Project leader (W. Atwood Principal Investigator, NIH 5-27961).
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).
2011-2013 DOD-CDMRP Exploration Hypothesis Development Award (TS100067; $100,000)
Title: Determining Changes in Neural Circuits in Tuberous Sclerosis.
Role: Principal Investigator.
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.
2010-2013 NIH/NCRR RI Hospital COBRE Center for Stem Cell Biology
Competitive Proposal Submission for Full Project (701-1960; $450,000)
Title: Determining the Transcriptional Regulation and Cell Signaling Events that Shape the Molecular Identity of Dopamine Neuron Progenitors and Specify Subtypes of Midbrain Dopamine Neurons.
Role: M. Zervas Project Leader (P. Quesenberry Principal Investigator, NIGMS 8P20GM103468-04)
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.
2010-Present Richard B. Salomon Faculty Research Award (2-34310; $15,000)
Title: Genetic Dissection of Midbrain Dopamine Neuron Diversity.
Role: Principal Investigator
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.
Hagan N, Guarente J, Ellisor D and Zervas M (2017). The temporal contribution of the Gbx2 lineage to cerebellar neurons. Front Neuroanat 11:50. doi: 10.3389/fnana.2017.00050 (PMID: 28785208).
Brown S and Zervas M (2017). Temporal expression of Wnt1 defines the competency state and terminal identity of progenitors in the developing cochlear nucleus and inferior colliculus. Front Neuroanat 11:67. doi: 10.3389/fnana.2017.00067 (PMID: 28878630).
Dingle YL, Xiong KB, Machan JT, Seymour KA, Ellisor D, Hoffman-Kim D, Zervas M (2016). Quantitative analysis of dopamine neuron subtypes generated from mouse embryonic stem cells. bioRxiv doi:http://dx.doi.org/10.1101/093419.
Normand EA, Crandall SR, Thorn CA, Murphy EM, Voelcker B, Browning C, Machan JT, Moore CI, Connors BW, Zervas M (2013) Temporal and mosaic Tsc1 deletion in the developing thalamus disrupts thalamocortical circuitry, neural function, and behavior. Neuron 78(5):895-909 (PMID: 23664552).
Yang J, Brown A, Ellisor D, Paul E, Hagan N, Zervas M (2013) Dynamic temporal requirement of Wnt1 in midbrain dopamine neuron development. Development 140(6):1342-1352 (PMID: 23444360).
Ellisor D, Rieser C, Voelcker B, Zervas M (2012) Genetic Dissection of Midbrain Dopamine Neuron Development in vivo. Dev. Biol. 372:249-262 (PMID:23041116).
Hagan N, Zervas M (2012) Wnt1 expression temporally allocates upper rhombic lip progenitors and defines their terminal cell fate in the cerebellum. Mol. Cell Neurosci.49:217-229 (PMCID: PMC3351839).
Hayes L, Zhang Z, Albert P, Zervas M*, Ahn S* (2011) The timing of Sonic Hedgehog and Gli1 expression segregates midbrain dopamine neurons. J. Comp. Neurol. 519:3001-3018 (PMCID: PMC3154975). *Co-corresponding authors.
Brown A, Machan JT, Zervas M (2011) Molecular organization and timing of Wnt1 expression define cohorts of midbrain dopamine neuron progenitors in vivo. J. Comp. Neurol. 519:2978-3000 (PMCID: PMC3359795).
Luu B, Ellisor D, Zervas M (2011) The Lineage Contribution and Role of Gbx2 in Spinal Cord Development. PLoS ONE 6(6): e20940. doi:10.1371/ journal.pone.0020940 (PMCID: PMC3116860).
Ellisor D, Zervas M (2010) Tamoxifen dose response and conditional cell marking: Is there control? Mol. Cell Neurosci. 45:132-138. Selected scientific image featured on cover (PMID: 20600933).
Brown A, Brown B, Ellisor D, Hagan, N, Normand, E, Zervas, M (2009) A Practical Approach to Genetic Inducible Fate Mapping: A Visual Guide to Mark and Track Cells In Vivo. J Vis Exp, 43: pii: 1687, doi: 10.3791/1687 (PMCID: PMC2846818).
Ellisor D, Koveal D, Hagan, N, Brown, A, Zervas M (2009) Comparative analysis of conditional reporter alleles in the developing embryo and embryonic nervous system. Gene Expr Patterns, 9:475-489 (PMCID: PMC2855890).
Zervas M (2007) Genetics, Neurobiology, and Translational Medicine: The Future of Schizophrenia Research. White Paper, Johnson & Johnson Pharmaceutical Research and Development. 133pp., Role: researcher, author.
Joyner AJ, Zervas M (2006) Genetic inducible fate mapping in mouse: establishing genetic lineages and defining genetic neuroanatomy in the nervous system. Dev. Dynamics 235:2376-2385 (PMID: 16871622).
Zervas M, Blaess S, Joyner AJ (2005) Classical embryological studies and modern genetic analysis of midbrain and cerebellum development. Curr. Topics Dev. Biol., (Neural Development), 69:101-138. Invited review; Selected scientific image featured on cover (PMID: 16118800).
Zervas M, Opitz T, Edelmann W, Wainer B, Kucherlapati R, Stanton P (2005) Impaired Hippocampal Long-Term Potentiation (LTP) in Microtubule-Associated Protein 1B-deficient Mice. J. Neurosci. Res. 82:83-92 (PMID: 16243598).
Zervas M, Millet S, Ahn S, Joyner AJ (2004) Cell behaviors and genetic lineages of the mesencephalon and rhombomere 1. Neuron 43:345-357 (PMID: 15294143).
Zervas M, Somers KL, Thrall MA, Walkley SU (2001) Critical role for glycosphingolipids in Niemann-Pick disease type C. Curr. Biol. 11(16):1283-1287 (PMID: 11525744).
Zervas M, Dobrenis K, Walkley SU (2001) Neurons in Niemann-Pick disease type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations. J. Neuropathol. Exp. Neurol. 60(1):49-64 (PMID: 11202175).
Walkley SU, Zervas M, Wiseman S (2000) Gangliosides as modulators of dendritogenesis in normal and storage disease-affected pyramidal neurons. Cereb. Cortex 10(10):1028-1037 (PMID: 11007553).
Zervas M and Walkley SU (1999) Ferret pyramidal cell dendritogenesis: changes in morphology and ganglioside expression during cortical development. J. Comp. Neurol. 413(3):429-448 (PMID: 10502250).
Walkley SU, Siegel DA, Dobrenis K, Zervas M (1998) GM2 ganglioside as a regulator of pyramidal neuron dendritogenesis. Annals of the NY Academy of Science 845:188-199 (PMID: 9668352).
Edelmann W, Zervas M, Costello P, Roback L, Fischer I, Hammarback JA, Cowan N, Davies P, Wainer B, Kucherlapati R (1996) Neuronal abnormalities in microtubule-associated protein 1B mutant mice. Proc. Natl. Acad. Sci. USA 93:1270-1275 (PMID: 8577753).
|2000||PhD||Albert Einstein College of Medicine|
|1996||MS||Albert Einstein College of Medicine|
|1993||BS||University of Massachusetts|
|Connors, Barry||L. Herbert Ballou University Professor of Neuroscience|
|Freiman, Richard||Associate Professor of Medical Science|
|Machan, Jason||Associate Professor of Surgery (Research), Associate Professor of Orthopaedics (Research)|
|Moore, Christopher||Associate Director of the Carney Institute of Brain Science, Professor of Neuroscience|