Research Article: Nuclear Receptor Unfulfilled Regulates Axonal Guidance and Cell Identity of Drosophila Mushroom Body Neurons

Date Published: December 22, 2009

Publisher: Public Library of Science

Author(s): Suewei Lin, Yaling Huang, Tzumin Lee, Brian D. McCabe.

Abstract: Nuclear receptors (NRs) comprise a family of ligand-regulated transcription factors that control diverse critical biological processes including various aspects of brain development. Eighteen NR genes exist in the Drosophila genome. To explore their roles in brain development, we knocked down individual NRs through the development of the mushroom bodies (MBs) by targeted RNAi. Besides recapitulating the known MB phenotypes for three NRs, we found that unfulfilled (unf), an ortholog of human photoreceptor specific nuclear receptor (PNR), regulates axonal morphogenesis and neuronal subtype identity. The adult MBs develop through remodeling of γ neurons plus de-novo elaboration of both α′/β′ and α/β neurons. Notably, unf is largely dispensable for the initial elaboration of γ neurons, but plays an essential role in their re-extension of axons after pruning during early metamorphosis. The subsequently derived MB neuron types also require unf for extension of axons beyond the terminus of the pruned bundle. Tracing single axons revealed misrouting rather than simple truncation. Further, silencing unf in single-cell clones elicited misguidance of axons in otherwise unperturbed MBs. Such axon guidance defects may occur as MB neurons partially lose their subtype identity, as evidenced by suppression of various MB subtype markers in unf knockdown MBs. In sum, unf governs axonal morphogenesis of multiple MB neuron types, possibly through regulating neuronal subtype identity.

Partial Text: The brain consists of neurons that are wired in specific patterns, and establishing a complex brain involves multiple tightly regulated developmental processes. In Drosophila, it starts with birth of neuroblasts (Nbs) with specific fates that are largely acquired through spatial patterning [1]. The Nbs then proliferate to produce multiple neuron types often in an invariant sequence [2], [3]. Post-mitotic neurons subsequently undergo extensive morphogenesis and some neurons remodel to form the circuitry [4], [5]. Although these basic processes are known, the detailed mechanisms that govern each step of brain development remain only partially resolved. Identifying more genes required for the various aspects of brain development is essential for elucidating further how the complex brain develops.

Silencing individual NRs through development of the MBs by transgenic miRNAs has allowed us to identify unf as another NR (in addition to EcR, usp, and tll) that regulates MB development. Previously, unf was shown to be essential for the wing expansion and fertility of adult flies, and abundantly expressed in the developing MBs [49]. Here we studied the function of unf in further detail and learned that unf acts in all three major types of MB neurons to promote proper neuron subtype identity and axon guidance. Comparable axon stalling defects of adult MB neurons, as well as missing larval MB dorsal axonal branches were observed in unf mutant organisms (Bates et al., submitted), validating our study of unf’s mechanism of action by targeted RNAi.



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