Investigation of the cellular and molecular mediators of adult neurogenesis

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Regeneration is often referred to as the 'holy grail' in scientific and medical research and is truly a fascinating feat in the central nervous system (CNS). Indeed, the successful replacement or regrowth of adult neurons in fully developed and highly integrated circuits is a phenomenon that occurs in only select vertebrate species. Mammals, for example, are generally incapable of adult regeneration and undergo neurogenesis (the birth of new neurons) in only a few restricted regions within the brain. In contrast, adult zebrafish undertake a vigorous regenerative process throughout the brain and spinal cord following CNS injury and maintain many neurogenic regions throughout their lifetime. The molecular factors responsible for neurogenesis and regeneration in this species, and what makes them unique from mammals, are largely unknown. The identification of essential neurogenic factors will provide needed insight into the molecular mechanisms that instruct neurogenesis in adult vertebrates and shed light on the evolutionary differences between natural `regenerators' and `non-regenerators'. Our current knowledge of adult neurogenesis is fragmented and largely derived from studies of the few neurogenic sites within the mammalian brain. In addition, very little is known about the essential intercellular relationships that largely govern adult neurogenesis, particularly those between subtypes of glial cells, and damaged or new neurons. Characterization of neurogenesis in the zebrafish spinal cord, with an emphasis on glial physiology and signaling, will therefore make a novel and important contribution to this field. Our short-term goals will work to address the following fundamental questions: what molecular factors govern regeneration in the zebrafish spinal cord; what homeostatic or neuroprotective roles to glial cells play in this system; and finally, do inflammatory signals associated with injury set the stage for regeneration? Here, we focus on the purinergic signaling family, the most ubiquitous and evolutionarily conserved family of signaling proteins in the CNS, but also the most unknown. We also aim to make direct comparisons to the mammalian microenvironment to gain insight into both the cellular and molecular components that prevent regeneration in this species. These studies offer an important prelude to subsequent, long-term goals aimed at discerning the appropriate choreography of signals that are responsible for regulating neural growth, development and neuroplasticity. Unraveling the cellular and molecular integration that drives these processes in zebrafish will be an invaluable step in understanding the evolutionary diversity of nervous system regeneration.