Mechanisms of cyclical degeneration and regeneration in an avian model system

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PROJECT SUMMARY A central goal of regenerative medicine is to understand how cells functionally integrate into existing tissues to restore homeostasis and behavior. Studies of regeneration following tissue damage in a group of ~6 species have made considerable advances towards this goal by uncovering mechanisms that promote proliferation, fate specification, and new cell survival. Pursuing these mechanisms, however, has revealed an underlying problem: how tissue re-patterning is limited to provide functional restoration and the re-establishment of homeostasis without detrimental overgrowth. To understand how growth and patterning are limited, and conversely, how tissues regress controllably will require broadening the systems in which these phenomena are examined to include models of natural, cyclical and highly stereotyped re-growth and degeneration. One such system – seasonally breeding songbirds – offers an outstanding opportunity to test mechanistic hypoth- eses of growth and degeneration and how events and outcomes at molecular and cellular levels impact higher- level anatomy and behavior. This lab makes use of two different songbird species: Gambel’s white-crowned sparrow (Zonotrichia leugophrys gambelli) and the domesticated canary (Serinus canaria domestica). White- crowned sparrows are advantageous in having dramatic cycles of seasonal degeneration and regeneration of the neural circuit that controls singing behavior; an extensive literature detailing their natural history; and high tractability for experimental analyses due to their natural abundance and robustness in the lab. Canary breeds, each having unique singing abilities and well-documented genetics, promise the ability to link historical selection for particular allelic variants to regenerative form and function, and plasticity at the level of individuals and populations. Exploiting the natural and dramatic degeneration–regeneration cycles in sparrows this proposal aims to determine how cell death: (i) influences generation of new cells to limit total growth of neural tissue and (ii) is finely tuned to prevent excessive degeneration of tissue and behavior while maintaining competency for a return to homeostasis and subsequent plasticity. Exploiting the tight genetic control imposed by breeders in selecting for exaggerated singing in canaries, the work aims to determine how diversification of behavior arose from modifications to the balance between degeneration and regeneration, and how genetic changes translate to cellular plasticity and emergence of novel behavior. Towards these goals, this program will use a highly integrative and complementary set of approaches – including pharmacological manipulations of intact neural circuits in freely behaving birds; classic cellular, molecular, and histological analyses; and state- of-the-art genomic approaches – to interrogate the cellular, molecular, and evolutionary mechanisms regulating tissue patterning and homeostasis. Uncovering proximate and ultimate mechanisms underlying tissue remodeling will add foundational knowledge to our understanding of hypertrophy and degenerative diseases and may reveal new ways by which lost or damaged tissues can be replaced in a clinical context.