| Laboratory of Genetics |
Intramural Program Investigators ^ Home ^ |
| David Schlessinger, Ph.D., Senior Investigator Chief, Laboratory of Genetics and Chief, Human Genetics Section |
 Dr. Schlessinger received his Ph.D. from Harvard University in 1960. Following postdoctoral training at the Pasteur Institute in Paris, he joined Washington University in St. Louis, where he served as Professor of Molecular Microbiology, Genetics, and Microbiology in Medicine until his move to NIA in September, 1997. He has contributed both to microbial and human genome studies. He has served as President of the American Society for Microbiology in 1995, and as the Director of the Human Genome Center at Washington University from 1987-97. During his tenure as Center director, he oversaw the development of the X chromosome map and of much related technology, with the concomitant finding of a number of disease genes. He is currently a councillor of the Human Genome Organization (HUGO) International, and President, HUGO Americas.Research Interests: The Human Genetics Section The program is designed to study embryonic and developmental events critical for the aging of specialized mammalian cells and concomitant aging-related phenomena. |
| 1. Technologies: We aim to understand tissue- and developmentally-restricted expression of selected genes at the level of RNA expression, gene regulation in chromatin, and protein diversity (proteomics), and to use mouse models to determine the physiological roles of the genes. Technologies being adapted include the generation of constructs for knock-out mice and the definition of regulatory element functions, using recombineering-based approaches in the Gene Recovery and Analysis Unit, headed by Ramaiah Nagaraja. The Unit has also generated knockout constructs for selected transcription factors involved in early embryonic development for the Developmental Genomics and Aging Section; and has implemented proteomics approaches, using mass spectrometry to profile gene expression at the protein level in mouse models. The study of regulatory processes is being extended to analyses of open and closed chromatin and histone modifications, projected for the genes recovered in chromatin form in artificial chromosomes. These techniques will be used, for example, to assess the role of the placental-specific gene (PLAC1) in fetal well-being and will be applied to analyze the long range regulation of PLAC1 and other relevant genes |
| 2. Areas of Research: Projects are designed to identify and characterize cohorts of genes involved in selected processes, using a "genome approach" to developmental phenomena. The approach starts from human inherited conditions and relevant embryological studies in mouse models (where sets of genes from embryonic stages can be easily assessed, and knockout technologies are available) and attempts to distinguish the factors responsible for the initiation and maintenance of the processes of interest. Examples of model systems under study in the Human Genetics Section include: |
| Premature Ovarian Failure. The progressive depletion of oocytes leads to the aging-related phenomenon of menopause. Its acceleration or anticipation define premature ovarian failure (POF), which occurs in up to 5% of women. Current work in the laboratory has identified part of a mechanism that may sustain the reproductive competence of the ovary based on the maintenance of gene activities that are initiated during embryo-fetal development. A subset of women with POF have a defect that is also associated with eyelid dysplasia (BPES, the blepharophimosis-ptosis-epicanthus inversus syndrome). We identified a "winged helix" transcription factor, FOXL2, that is mutated to cause both the eyelid and ovarian follicle defects. In correlated developmental work, a mouse knockout model has been developed that recapitulates features of BPES. Systematic studies have defined gene cohorts specifically expressed during the development of ovarian follicles, including the target genes controlled by FOXL2. In the absence of FOXL2, all follicle formation and ovary maturation fails, and partial sex reversal ensues. Thus, FOXL2 is involved in ovary formation, in the regulation of female reproductive life span, and in the maintenance of female sex determination - thereby providing a mechanism for the continued action of developmental processes in female reproductive competence. |
| Skin Appendage Formation. Teeth, hair follicles and sebaceous and sweat glands, the latter being essential for regulation of the body temperature, are defective or lacking in patients with X-linked anhidrotic ectodermal dysplasia (EDA). We identified the gene mutated in most of these patients and characterized the developmental course of the anomalies affecting the Tabby mouse, an experimental model for the human condition. We showed that EDA is required transiently during development to initiate skin appendage formation, yet maintains a trophic effect throughout life. Transgenic experiments found that in mice, one EDA isoform can differentially affect distinct hair types, rescue sweat glands, and also prevent ocular surface disease that is otherwise seen in the mice (and in EDA-deficient mice patients). Further study is aimed at understanding the aging-related defects in skin appendages, which are extensive and highly diverse among individuals. Expression profiling has revealed downstream NF-kB-dependent pathways, including the dependence of hair type on the non-canonical lymphotoxin-beta pathway. EDA thereby provides an entree to an embryonic branch point that leads to the formation of the whole range of skin appendages and functions. |
| Cartilage Hair Hypoplasia. In this case, a gene encoding an RNA is mutated. The RNA functions in a complex with proteins to participate in the formation of ribosomal RNA and mitochondrial RNA species, and in the mutant, aberrant cartilage and defective, sparse hair are seen. Studies are defining the protein complement of the normal complex involved in RNA processing, and a mouse model is being constructed that reproduces features of the human condition, in order to define better the pathological defects caused by the mutation. |
| Population-based Study of Genetic Risk Factors. More proximal to complex human diseases, an extensive collaborative project is studying a favorably inter-related population in Sardinia to determine critical genes involved in aging-related traits, with the long-term aim of promoting patient benefit. To date, 98 quantitative traits, including personality traits and risk factors for cardiovascular disease, have been assessed on 6,162 participants ages 14-102, comprising over 60% of the population of a cluster of 4 towns. The population is highly inter-related, including, for example, about 5,000 sib pairs. This has facilitated the determination that heritability of each trait is sufficient to anticipate the finding of any genetic locus that contributes 3% or more to the variance of trait values. As a first step to finding such loci and associated alleles in genes, full genome scans with up to 500,000 single nucleotide polymorphisms (SNPs) are now in progress for all participants. |
| Contact Information: Laboratory of Genetics Biomedical Research Center, 10C214 251 Bayview Boulevard, Suite 100 Baltimore, MD 21224-6825 Phone 410-558-8338 Fax 410-558-8331 E mail schlessingerd@mail.nih.gov For more information about the Laboratory: http://www.irp.nia.nih.gov/branches/lg/lg.htm |
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