Heads of Laboratories
Investigator, Howard Hughes Medical Institute
James and Marilyn Simons Professor
Laboratory of Molecular Biology
Research in Dr. Heintz’s laboratory aims to identify the genes, circuits, cells, macromolecular assemblies, and individual molecules that contribute to the function of the mammalian brain and to its dysfunction in disease. Dr. Heintz and his colleagues use novel approaches based on the manipulation of bacterial artificial chromosomes (BACs) to investigate the mammalian brain’s histological and functional complexities in vivo.
Research in the Heintz laboratory focuses on the following four areas:
Genetic dissection of central nervous system (CNS) cell types and circuits. The Heintz laboratory invented DNA engineering by homologous recombination in E. coli (“recombineering”) and demonstrated that engineered BAC transgenes can be reliably expressed in defined CNS cell types in vivo. Collaborating with Mary E. Hatten, the Heintz laboratory launched the NINDS Gene Expression Nervous System Atlas project (www.gensat.org), a large-scale screen using BAC transgenic mice to create an atlas of cellular CNS gene expression. It provides detailed anatomical data on cell types targeted in over 1,500 BAC transgenic mouse lines and provides a library of verified BAC vectors and transgenic mouse lines.
Translational profiling of CNS cell types in health and disease. The Heintz laboratory, in collaboration with Paul Greengard, developed the translating ribosome affinity purification (TRAP) technique. By fusing an affinity tag to a ribosomal protein, TRAP enables the isolation of bound messenger RNAs from a targeted cell type without requiring isolation of that cell type from tissue. The laboratory employs bacTRAP transgenic mice and TRAP profiling to determine molecular constitutions of a wide variety of cell types in the mouse brain and to determine the molecular phenotypes of select cell types in mouse models of autism spectrum and other disorders. TRAP profiling has led to the definition of biochemical pathways whose altered activity contributes to the pathophysiology of CNS disorders.
Epigenetic regulation of the neuronal genome: the role of 5-hydroxymethylcytosine (5hmC). Over the last several decades, a strong connection between the presence of 5-methylcytosine (5mC), chromatin organization, and gene expression has been established. The Heintz laboratory discovered 5hmC is present in the mammalian genome and specifically enriched in neurons. Dr. Heintz and his colleagues are addressing the potential implications of 5hmC, a novel epigenetic mark not previously observed in metazoans. Their recent finding that the Rett syndome protein MeCP2 binds with high affinity to 5hmC has stimulated interest in the possible role of 5hmC in neurological disease.
Biochemical mechanisms of neuronal function. As part of investigations into the macromolecular assemblies that govern neuronal function in their native context, the Heintz laboratory, in collaboration with Brian T. Chait, has identified protein components of these complex machines using mass spectroscopy. For example, they characterized the biochemical properties of specific synapse types in the mammalian brain, revealing fundamental biochemical differences between excitatory and inhibitory synapses. Studies such as this demonstrate that in vivo biochemical profiling provides an important avenue toward deciphering the complex phenotypes encountered using conventional genetic perturbations.
B.A. in biology, 1974
Ph.D. in biological sciences, 1979
University at Albany, State University of New York
Washington University, 1979–1982
Assistant Professor, 1983–1987
Associate Professor, 1987–1992
The Rockefeller University
Assistant Investigator, 1987–1988
Associate Investigator, 1988–1992
Howard Hughes Medical Institute
Pew Biomedical Scholar, 1985
Junior Faculty Research Award, American Cancer Society, 1986
Fellow, American Association for the Advancement of Science
Nakajima, M. et al. Oxytocin modulates female sociosexual behavior through a specific class of prefrontal cortical interneurons. Cell 159, 295–305 (2014).
Mellén, M. et al. MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell 151, 1417–1430 (2012).
Schmidt, E.F. et al. Identification of the cortical neurons that mediate antidepressant responses. Cell 149, 1152–1163 (2012).
Kriaucionis, S. and Heintz, N. The nuclear DNA base 5-hydroxymethyl-cytosine is present in Purkinje neurons and the brain. Science 324, 929–930 (2009).
Heiman, M. et al. A translational profiling approach for the molecular characterization of CNS cell types. Cell 135, 738–748 (2008).