Marc E. Lalande, Ph.D.

Professor and Chair, Genetics and Developmental Biology
Senior Associate Dean for Research Planning and Coordination
Academic Office Location:
Genetics & Developmental Biology
University of Connecticut Health Center
263 Farmington Avenue
Farmington, CT 06030-6403
Phone: 860-679-8350
Fax: 860-679-8345
Email: lalande@uchc.edu
Website(s): Department of Genetics and Developmental Biology
Genetics & Developmental Biology Graduate Program
Skeletal, Craniofacial & Oral Bio. Grad. Program

Marc Lalande, Ph.D., holds the Physicians Health Services Chair in Genetics and Developmental Biology. He is professor and chairman of the Department of Genetics and Developmental Biology, and Senior Associate Dean for Research Planning and Coordination at the University of Connecticut School of Medicine. He is also Director of the University of Connecticut Stem Cell Institute and its Institute for Systems Genomics.

Education
DegreeInstitutionMajor
Ph.D.University of TorontoMedical Biophysics
M.S.University of TorontoMedical Biophysics
B.S.Laurentian UniversityPhysics

Post-Graduate Training
TrainingInstitutionSpecialty
FellowshipChildren's Hospital and Department of Pediatrics, Harvard Medical SchoolResearch Fellow, Genetics Division

Awards
Name of Award/HonorAwarding Organization
Dr. Claudia Benton Award for Scientific ResearchAngelman Syndrome Foundation
Health Care Hero Award for Advancements in Healthcare Innovation Hartford Business Journal
Elected to the Connecticut Academy of Sciences and EngineeringConnecticut Academy of Sciences and Engineering
Dr. Lalande’s research is on the role of epigenetics in disease and development. Epigenetics refers the study of heritable changes in gene function that occur without an alteration in DNA sequence. The Lalande laboratory is focused on translational studies of human epigenetic disorders using murine models and human induced pluripotent stem (iPS) cell technology.

Angelman syndrome is a neurogenetic disorder characterized by severe mental retardation, "puppet-like" ataxic gait with jerky arm movements, seizures, EEG abnormalities, hyperactivity and bouts of inappropriate laughter. Individuals with AS lack a normal maternal copy of the gene encoding ubiquitin protein ligase E3A (UBE3A). UBE3A is transcribed only from the maternal allele in brain with the paternal copy of UBE3A being silenced due to an epigenetic phenomenon called genomic imprinting. Genes that are subject to genomic imprinting are expressed exclusively from one parental allele. This process is said to be epigenetic because it involves heritable changes in gene function that occur without a change in the sequence of DNA.

a) The role of Ube3a in the mammalian stress response. How the loss of UBE3A in brain causes AS is not clear. To study this problem, we have derived two different stable mouse cell lines with shRNA-mediated Ube3a knockdown. Knockdown of Ube3a in both NIH3T3 and P19 embryonic carcinoma cells resulted in increased resistance to both doxorubicin- and paraquat-induced cell death thus indicating that UBE3A functions to promote cell death in response to genotoxic and oxidative stress. Ectopic expression of wild type but not a mutant form of UBE3A, restored doxorubicin sensitivity to Ube3a-deficient NIH3T3 cells, suggesting that the ubiqitin ligase activity of UBE3A is essential for regulating the genotoxic cell death response. We have also generated a mouse model with a "humanized" Ube3a mutation consisting of a 2 bp deletion in the coding region. Using primary cells derived from these mice, we have observed that sensitivity to doxorubicin-mediated genotoxic stress is directly related to the levels of UBE3A protein in murine embryonic fibroblasts (MEFs) derived from mice homozygous, heterozygous and wild type for the Ube3a mutation. Given these results, we conclude that UBE3A may function in the ubiquitin stress response pathway and that the phenotypic manifestations of AS may be due, at least in part, to increased levels of free ubiquitin in the brain.

b) Induced pluripotent stem (iPS) cells models of AS. The recent discovery of genomic reprogramming of human somatic cells into induced pluripotent stem cells (iPS) offers an innovative and relevant approach to the study of human genetic and neurogenetic diseases such as Angelman syndrome. By reprogramming somatic cells from patient samples, cell lines can be isolated that self-renew indefinitely and have the potential to develop into multiple different tissue lineages. Additionally, the rapid progress of research on human embryonic stem cells (hESCs) has led to the development of sophisticated in vitro differentiation protocols that closely mimic mammalian development. We have perfected the experimental approaches for somatic cell reprogramming by introducing four reprogramming factors via retroviral vectors into dermal fibroblasts. We are deriving iPS cells from dermal fibroblasts from normal control and Angelman syndrome patients with the goal of differentiating the iPS cells to generate human Angelman syndrome neurons. Using these patient-specific fibroblasts and neurons, we are modeling the effects of specific human gene defects in vitro and studying how they influence genomic imprinting and UBE3A expression. Ultimately, the development of this technology will allow us to generate a human neuronal cell culture model of AS for testing small molecules or other potential therapies.

Accepting students for Lab Rotations: Summer '13, Fall '13, Spring '14

A model of post-traumatic stress disorder in a tissue culture dish

Marc Lalande and Kristen Martins-Taylor, Department of Genetics and Developmental Biology and University of Connecticut Stem Cell Institute

Major risk factors for developing post-traumatic stress disorder (PTSD) are variants in genes active in the stress-response system and past childhood abuse. There is a significant need to understand such gene-environment effects in order to develop better treatments and preventive programs. We are investigating the epigenetic mechanisms that contribute to the predisposition to PTSD with a focus on FK506 binding protein 5 (FKBP5), an important regulator of the cortisol-glucocorticoid receptor (GR) complex and the hypothalamic-pituitary-adrenal (HPA) axis. In particular, the rs1360780 A/T allele enhances the interaction between intron 2 and the promoter and increases FKBP5 induction thus conferring risk for the development of PTSD. The C/G allele, on the other hand, has been deemed protective. Using human embryonic stem cells (hESCs) and gene editing technology, we are constructing an in vitro model of PTSD predisposition by generating hESCs that carry, respectively, the risk and protective rs1360780 alleles of FKBP5. We are generating isogenic pairs of hESCs carrying the FKBP5 risk variants via custom designed transcription activator-like effector nucleases (TALENs). The cell lines that are homozygous for the FKBP5 rs1360780 A (risk) and G (protective) alleles will be differentiated into neural progenitors (NPs) and subjected to stress by treatment with the glucorticoid receptor agonist dexamethasone. Our goal is to compare how the FKBP5 risk and protective variants alter the stress response by assaying for differences DNA methylation and post-translational chromatin modifications at the FKBP5 locus and across the genome.

Journal Articles

Book Chapters

  • Molecular Analysis of the Angelman/Prader-Willi Syndromes
    Lalande M, Wagstaff J, Knoll JHM (1995) Techniques and Applications of Genome Research 69-82
  • Metaphase chromosome flow sorting and cloning rationale, approaches and applications
    Latt SA, Lalande M, Flint A, Harris P, Muller U, Donlon T, Tantravahi U, Bruns G, Kurnit D, Neve R, Kunkel L (1989) Flow Cytogenetics 243-256
  • Molecular Genetics Via Flow Cytometry
    Van Dilla MA, Kamarck M, Lalande M (1987) Flow Cytometry and Sorting
  • Sorting, cloning, and analysis of specific human chromosomes
    Latt SA, Kanda N, Kunkel LM, Lalande M, Alt F, Kohl N, Bruns G, Aldridge J, Schreck R, Tantravahi U (1984) Chromosomes Today VII 15-22
  • Construction, analysis, and utilization of recombinant phage libraries enriched for the human X chromosome by fluorescence activated flow sorting
    Latt SA, Kunkel LM, Tantravahi U, Aldridge J, Lalande M (1983) Banbury Report 14: Recombinant DNA Applications to Human Disease 189-196
  • Contruction, analysis and utilization of recombinant phage libraries obtained using fluorescence activated flow sorting
    Latt SA, Kunkel LM, Tantravahi U, Aldridge J, Lalande M (1983) Recombinant DNA and Medical Genetics 35-47

Letters

Notes

Reviews

Title or AbstractSponsor/EventDate/YearLocation
Animal Models and Their Value in Predicting Drug Efficacy and ToxicityNew York Academy of Sciences2011New York, NY
Patient-Specific Induced Pluripotent Stem Cells for the Study of Neurological DiseasesNew York Academy of Sciences2011New York, NY
Induced pluripotent stem (iPS) cell models of human neurogenetic disordersDepartment of Human Genetics, McGill University2010Montreal, Canada
Induced pluripotent stem cells - Potential and reliabilitySMi Stem Cells Conference 2010London UK
An in vitro model of Angelman syndrome via Induced pluripotent stem cell technologyThe Genome Center and Epigenomic Group, University of California Davis2010Davis, CA
Derivation of live Angelman syndrome neurons from induced pluripotent stem (iPS) cellsAngelman Scientific Symposium2010Chapel Hill, NC
Association des cytogénéticiens de langue française2010Aix-en-Provence, France
Induced pluripotent stem cell models of Prader-Willi syndrome and other neurogenetic disorders2010Washington DC
Somatic cell reprogramming to create an in vitro model of Angelman syndromeEpigenetics and Cell Fate research unit (UMR7216 ) at University of Paris 2009Paris, France
In vitro models of human neurogenetic and imprinting disorders derived via induced pluripotent stem (iPS) cell technologyM2 Stem Cells Lecture, Université Paris Diderot2009Paris France