Brain Signaling

The major goal of the research proposal is to further develop our understanding of the development of the vertebrate central nervous system. Early in the development of all vertebrates, the precursor to the central nervous system is induced on the dorsal side of the embryo as an undifferentiated sheet of cells called the neural plate. A series of molecular signals from the posterior of the embryo sequentially subdivides this sheet of cells into functional domains, and establishes conserved signaling centers at stereotypical regions in the developing brain. These signaling centers are a source of secreted factors that are essential to establish boundaries in the developing brain for normal patterning. Deciphering the mechanisms behind vertebrate brain regionalization is highly complex as vertebrates have many duplicates of genes with fundamental roles in developmental neurobiology. Often duplicate genes have redundant roles making functional analyses complex and hard to interpret.  Additionally many of these genes play other developmental roles early in embryogenesis that can lead to complications in interpretation of functional studies. Dr. Lowe’s lab proposes to study the interactions of homologous suites of genes in an animal with a more simple body plan, closely related to vertebrates. The hemichordates have a simple nervous system, yet have a conserved suite of genes involved in regionalization of the nervous system, strongly resembling the relative expression domains of the same genes during vertebrate neural development. However, there is no gene duplication and usually only one domain of gene expression in the developing ectoderm making functional experiments easier to interpret. They hope these experiments will reveal fundamental insights into brain patterning that will guide future experiments in vertebrate development.
Dr. Lowe proposes to investigate how the nervous system is patterned during development. In particular, he will study the establishment of identity within the neural plate that forms the brain and spinal cord. His lab has elected to use the acorn worm to investigate the regulation and formation of brain signaling centers. There are fundamental anatomical differences between the acorn worm’s simple nerve net and the elaborate centralized nervous system in vertebrates such as humans. However, we have already shown a rich conservation in the patterning mechanisms of the acorn worm and vertebrate nervous systems. By unraveling the fundamental genetic interactions responsible for regionalization of the nerve net in hemichordates, they anticipate this will help inform and guide experiments in vertebrate neural systems where gene duplication and functional redundancy make interpretation of experimental data difficult. By use of a simple system, this work will identify highly conservative elements of brain patterning, and hopefully reveal basic principles of brain development which have not been apparent from studies of vertebrates. A more profound understanding of brain development clearly leads to potential for better approaches to treatment of neurodevelopmental abnormalities. If we are to design therapeutic strategies for the treatment of behavioral disorders, we must also understand the genetic mechanisms underlying these conditions. This work will have additional benefits beyond these clinical applications, as comparisons between the acorn worm and vertebrates will begin to uncover the nature of our ancestor’s nervous system and the mechanisms by which our own elaborate neuroanatomy evolved.

Other Grants

Sarah C. Goetz, Ph.D., Duke University
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Erin M. Gibson, Ph.D., Stanford University
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Yvette Fisher, Ph.D., University of California, Berkeley
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Byoung Il Bae, Ph.D., University of Connecticut
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