Postdoctoral, Dept. of Embryology, Carnegie Institution of Washington, 2003
Postdoctoral, Skirball Institute of Biomolecular Medicine, New York University, 1999
Ph.D., University of Michigan, 1996
Zebrafish neural tube labeled with microtubule marker (Acetylated tubulin)
The Brewster laboratory is interested in understanding the mechanisms that underlie central nervous system birth defects, such as spina bifida, which results from impaired neural tube formation. In addition, we have recently begun to investigate how the brain responds to low oxygen (hypoxia or anoxia), with the ultimate goal of identifying potential therapeutic targets for stroke. We use the zebrafish as a model system to carry out these studies as this vertebrate organism lends itself well to gene discovery, embryonic and genetic manipulations and live imaging.
1. Studies on neural tube formation. Neural tube defects are the most common severely disabling birth defects in the United States, with a frequency of approximately 1 in every 2000 births. NTDs are thought to be caused by a combination of genetic and environmental factors, neither of which are well understood. We expect that our research on the genetic pathways that control neurulation (neural tube formation) will pave the way for translational research in preventing these birth defects. In additional to this clinical relevance, studies on neural tube formation offer the opportunity to explore fundamental questions at the interface of Cell and Developmental Biology. We have previously carried out an extensive analysis of the cellular behaviors that drive neurulation in the zebrafish. These studies now provide a foundation to explore the molecular mechanisms of neurulation. Briefly, we have found that neurulation in the zebrafish can be considered as a biphasic process that involves: 1. “neural convergence”, the ability of neural progenitor cells to migrate towards the midline and assemble into a chord-like structure and 2. “epithelialization”, the transformation of migratory neural progenitors with mesenchymal properties into stationary epithelial cells that have a clearly defined apico-basal axis. Epithelialization is a multi-step process that involves the formation of apical junctional complexes (tight junctions, adherens junctions) in addition to a complete reorganization of the cytoskeleton. Failure of either neural convergence or epithelialization results severe neural tube defects.
Ongoing projects focus on the identification of molecular pathways that control neural convergence. Through the study of a mutant called linguini in which the microtubule network is disrupted, we have found that stabilization of the microtubule network is essential for proper neural convergence. We are currently searching for molecules that stabilize microtubules during neurulation and have identified several microtubule-associated proteins and upstream regulators. In addition, we are investigating what signal(s) attract migrating neural progenitor cells towards the midline. Our ultimate goal is to screen patient cohorts with NTDs for causative mutations in the genes we have identified, as a means to identify novel genetic risk factors. We have also begun to investigate environmental factors that alter microtubule stability and cause neural tube defects. These combined approaches are expected to increase our understanding of the genetic and environmental factors that converge to cause NTDs by altering the microtubule cytoskeleton.
2. Studies on anoxia tolerance. Stroke is the third leading cause of death in the US. It is caused by impaired brain function due a temporary blockage of blood flow (ischemia). Cell death in the brain does not occur for several days following ischemic injury, providing a therapeutic window for treatment. However, no drugs have so far been developed that effectively prevent cell death.
Interestingly, some organisms, such as zebrafish embryos, exhibit a high level of tolerance to anoxia, surviving without oxygen for several hours up to a day. While the mechanisms of anoxia tolerance are mostly unknown, it is thought that brain ATP levels are maintained, despite the shutdown of oxydative phosphorylation, by decreasing the rate of ATP consumption. We are currently investigating the role of two proteins, AMP-activated protein kinase (AMPK) and Hypoxia-inducible factor alpha (Hif 1-alpha) in decreasing metabolic rates in the brain in response to anoxia, to conserve ATP levels. In the long term we intend to carry out a genetic screen to identify genes that mediate anoxia tolerance. These approaches will increase our understanding of the mechanisms underlying anoxia tolerance and may lead to the discovery or novel therapeutic targets for treatment of stroke.
Microtubule-associated protein 1b is required for shaping the neural tube. Jayachandran P, Olmo VN, Sanchez SP, McFarland RJ, Vital E, Werner JM, Hong E, Sanchez-alberole N, Molodstov A, Brewster RM. Neural Dev. 2016 Jan 18;11(1):1. doi: 10.1186/s13064-015-0056-4. PMID: 26782621
Jayachandran P., Hong E. and Brewster R. (2010). Labeling and imaging cells in the zebrafish hindbrain. J Vis Exp. PMID: 20689510.
Hong E., Jayachandran P. and Brewster R. (2010). The polarity protein pard3 is required for centrosome positioning during neurulation. Dev Biol., 341(2):335-45.
Harrington MJ, Chalasani K, Brewster R. (2010). Cellular mechanisms of posterior neural tube morphogenesis in the zebrafish. Dev Dyn., 239(3):747-62.
Harrington MJ, Hong E, Brewster R. (2009). Comparative analysis of neurulation: first impressions do not count. Mol Reprod Dev., 76(10):954-65.
Harrington MJ, Hong E, Fasanmi O, Brewster R. (2007) Cadherin-mediated adhesion regulates posterior body formation. BMC Dev Biol. 7:130.
Hong E., and Brewster R. (2006). N-cadherin is required for the polarized cell behaviors that drive neurulation in the zebrafish. Development 133:3895-3905.
Brewster R., Ruiz I., and Altaba A. (2000). Hexokinase I is a Gli2-responsive gene expressed in the embryonic CNS. Mech. Dev. 99:159-162.
Brewster R., Mullor JL, Ruiz I., and Altaba A. (2000). Gli2 functions in FGF signaling during antero-posterior patterning. Development 127:4395-4405.
Brewster R. and Dahmane N. (1999). Getting ahead of the organizer: anterior-posterior patterning of the forebrain. Bioessays 21:631-636.
Brewster R., Lee J., Ruiz I., and Altaba A. (1998). Gli/Zic factors pattern the neural plate by defining domains of cell differentiation. Nature 393:579-583.
Presidential Early Career Award for Scientists and Engineers (PECASE)
The National Science and Technology Council (NSTC)
Rachel M. Brewster Among Just 3 U.S. Biologists Nominated by NSF to Receive Presidential Early Career Award UMBC biologist Rachel M. Brewster received the nation’s top honor for promising young scientists, the Presidential Early Career Award for Scientists and Engineers (PECASE), which were recently announced at a White House ceremony. The PECASE provides up to five years of financial support to the honored scientists for research and community outreach. Awardees must be nominated by a participating federal agency or department. Brewster was one of just three U.S. biologists nominated by the National Science Foundation (NSF) who were selected for the PECASE. Brewster will use her PECASE funding to involve high school, undergraduate and graduate students from diverse backgrounds in her lab’s research. Brewster’s specialty is genetic analysis of zebrafish embryos to better understand the causes of birth defects of the brain and central nervous system, the most common of which is spina bifida, the leading cause of childhood paralysis in the United States. “It’s certainly an amazing honor to receive this award,” said Brewster. In her acceptance speech, Brewster thanked UMBC President Freeman Hrabowski as the catalyst for the University’s Meyerhoff Scholarship Program. The Meyerhoff Program has become known as a national model for drawing talented minority students into research careers that often begin under the mentorship of UMBC professors. “I have been very fortunate to work with some of these students in my lab,” said Brewster. She singled out UMBC alumna and former Meyerhoff Scholar Keisha John, who now attends the Watson Graduate School of Biological Sciences, as instrumental in producing some key data that made the award nomination possible. “This is a great honor for Rachel and the department,” said Lasse Lindahl, professor and chair of UMBC’s biological sciences department. “The award will make officials in the White House’s Office of Science and Technology and colleagues around the country more familiar with the quality of research at UMBC. We are very proud of Dr. Brewster and her accomplishments.” “Rachel Brewster is a wonderful colleague, an inspiring role model and a dedicated mentor to many students at UMBC,” said Lynn Zimmerman, professor of biology and vice provost for academic initiatives at UMBC. “She is a tremendous asset to UMBC’s biological sciences department and we are delighted to see her receive this well deserved recognition.” Brewster, an assistant professor of biological sciences at UMBC, received her Ph.D. from the University of Michigan and did postdoctoral work at the New York University’s Skirball Institute of Biomolecular Medicine and the Department of Embryology at the Carnegie Institution of Washington. The PECASE program recognizes outstanding scientists and engineers who show exceptional potential for leadership at the frontiers of knowledge early in their careers. President Bush honored a total of 60 young scientists for their extensive research accomplishments and for their noteworthy educational contributions at the ceremony.
Role of Zebrafish N-cadherin in Neurulation and Neuronal Differentiation
Our central nervous system (CNS) carries out highly complex functions, which enable us to sense our environment, think and coordinate movements. Not surprisingly, even slight perturbations in the proper assembly of the CNS can have a dramatic impact on our lives. The goal of this research proposal is to analyze the role of two critical genes, N-cadherin (N-cad) and bumpy brain (bpb), in CNS development, using the zebrafish as a model system. While N-cad encodes a cell adhesion molecule, the molecular identity of bpb is currently unknown. Both N-cad and bpb are essential for the shaping of the neural tube, the precursor of the CNS, and genetic evidence indicates that the products of these genes interact. In addition, N-cad appears to be required for the maintenance of stem cell-like populations in the CNS. The specific aims of this research proposal are to investigate, at a cellular and molecular level, how N-cad and bpb function and interact to mediate these processes. Since zebrafish CNS development bears multiple similarities to that of other vertebrates, these studies should reveal fundamental mechanisms underlying CNS development. The broader educational goals of this research proposal are to 1) expose students at all levels to basic research and foster an interest in research-related careers, 2) increase the participation of underrepresented minorities in the sciences. The first goal will be accomplished by recruiting high school students from neighboring schools to carry out research projects in the laboratory, participation of the PI and her students in science-related lecture series at these high schools and the creation of innovative curricular offerings. Finally, by leveraging the institutional strengths of the University of Maryland Baltimore County, the PI will continue to provide a nurturing and stimulating learning environment for students from underrepresented groups.
Regulation of cell polarity during neurulation
The posterior region of the neural tube in amniotes undergoes “secondary neurulation”, where a mesenchymal population of neural precursor cells first condenses into a solid medullary cord, undergoes a mesenchymal-to-epithelial transition and cavitates to form a lumen. Despite the high incidence of human posterior neural tube defects (1/1000 live births), the cellular and molecular mechanisms that mediate secondary neurulation remain for the most part unknown. The zebrafish is an ideal system in which to study neurulation, as it offers a combination of excellent imaging tools for investigating the cellular behaviors underlying morphogenesis and genetics to identify the essential molecules that regulate these behaviors. Moreover, evidence from our laboratory and others has demonstrated that the zebrafish embryo undergoes a form of secondary neurulation.Formation of the neural tube in the zebrafish is dependent on the ability of cells to polarize properly. Polarity is first manifested by the extension of directional membrane protrusions that drive neural cell convergence towards the dorsal midline. Once these mesenchymal cells have coalesced into a neural rod, they become epithelial and establish a clearly defined apico-basal axis. The overall goal of this proposal is to understand how cell polarity is regulated during neurulation and how disruption of this polarity perturbs both the morphogenetic movements that shape the neural tube and neural cytoarchitecture.