The Section on Genetics of Early Development is investigating the genetic requirements for the earliest stages of development using the model organism C. elegans. They are most interested in gamete differentiation, fertilization, and the signals to initiate embryonic development. To study these events, they have studied genetic mutants defective in each of these processes. They are also beginning to look at orthologs of disease genes that perturb early development.
Genetics of Organelle Biogenesis Section
The Genetics of Organelle Biogenesis Section studies the biogenesis and function of centrioles, non-membrane bound organelles that play key roles in cell division, motility, and signaling. A growing number of diseases including cancer, autosomal recessive primary microcephaly, and polycystic kidney disease, have been linked to defects in centriole number and/or function. Thus, their work will help shed light on the normal regulatory mechanisms governing centrioles and how these processes go awry in disease.
Genetics of Simple Eukaryotes Section
Reed B. Wickner, M.D., NIH Distinguished Investigator
The Genetics of Simple Eukaryotes Section uses S. cerevisiae to study infectious diseases, particularly prions (infectious proteins). By examining the structure of the amyloids underlying most yeast prions, and the genetics of prion propagation and generation we have obtained an understanding of how proteins can be the basis of genetic information propagation, discovered several means of curing prions, and obtained information that will likely be useful in studies of human amyloidoses.
The Pharmacology Section studies the polyamines—putrescine, spermidine, and spermine—which are major polybasic compounds in all living cells. These amines are important for many systems related to growth and differentiation. Researchers in this section investigate how these polyamines are synthesized, how their biosynthesis and degradation are regulated, their physiologic functions, and how they act in vivo. For this purpose, section scientists have constructed null mutants in each of the biosynthetic steps in both Escherichia coli and in S. cerevisiae. These mutants are unable to make these amines; hence, they are very useful tools to study the physiological effects of lacking these amines. Research in the section has demonstrated that the polyamines are required for the following functions: growth of the organisms, sporulation, maintenance of the killer dsRNA virus, protection against oxidative damage, protection against elevated temperatures, fidelity of protein biosynthesis, and maintenance of mitochondria. Additionally, scientists have constructed clones that overproduce the various enzymes and studied the sequence, structure, and regulation of these enzymes (e.g., ornithine decarboxylase, spermidine synthase, spermine synthase, and S-adenosylmethionine decarboxylase.
Physical Biochemistry Section
The Section on Physical Biochemistry is engaged in quantitative studies of effect of high concentrations of nominally inert small molecule and macromolecular cosolutes on the thermodynamic and hydrodynamic behavior of selected proteins and nucleic acids. The identification and characterization of such effects is essential for an understanding and quantitative prediction of the functional behavior of proteins and nucleic acids within complex physiological media. These studies are carried out both theoretically and experimentally, often using concepts and experimental tools developed in our laboratory.
Protein Chaperones and Amyloid Section
The Protein Chaperones & Amyloid Section identifies and characterizes cellular factors that influence propagation of the S. cerevisiae [PSI+] prion. [PSI+] is thought to be an amyloid form of Sup35, a protein involved in termination of protein synthesis. About two dozen human disorders, which include Type 2 diabetes and Alzheimer's disease, are associated with accumulation of amyloid forms of proteins. In addition to simply growing, transmissible [PSI+] particles, or prion "seeds", must replicate to be maintained in a growing yeast population. Research in this section provides a better understanding of how protein chaperones (Hsp70, Hsp40, and Hsp104) and TPR co-chaperones function in amyloid propagation. The normal function of this chaperone machine appears to promote amyloid propagation by breaking fibers into more numerous pieces, each of which can continue to propagate the amyloid structure. Section researchers have identified several mutations in these chaperones that variously affect the [PSI+] seeding process—findings that will improve understanding of the underlying molecular mechanisms.