Molecular Mechanisms that Differentiate Dendritic and Axonal Growth.

[摘要] The nervous system controls our perception, behavior, learning and memory. It consists of billions of cells called neurons. A neuron typically contains an information input compartment, termed the dendrites, and an output compartment, termed the axon. These two compartments of a neuron provides structural basis for signal transmission in the nervous system. Identifying the mechanisms that separate dendritic and axonal growth not only expands our understanding about the wiring of neural circuits, but also provides insights into designing treatment of neurological diseases. Recent studies, including those of our own, have uncovered two regulatory mechanisms that differentiate dendritic and axonal growth: dedicated mechanisms and bimodal mechanisms. Dedicated mechanisms regulate dendrite-specific or axon-specific growth; in contrast, bimodal mechanisms direct dendritic and axonal development in opposite manners. In this thesis, I first demonstrate that the evolutionarily conserved dual leucine zipper kinase (DLK; or Wnd in Drosophila), previously known to regulate axonal growth, regeneration and degeneration, functions as a bimodal regulator to promote axonal growth but restrain dendritic growth of class IV dendritic arborization (C4da) neurons in Drosophila larvae (Chapter 2). I then present a study by my colleagues and me, which identified a novel role of endogenous DLK/Wnd in organizing presynaptic structures at the axonal terminals (Chapter 3). These studies demonstrate that the diverse functions of DLK/Wnd are mediated by independent downstream components including different transcription factors, MAPKs, and scaffolding proteins (Chapters 2 and 3). In Chapter 4, I present that the cell adhesion molecule Dscam, whose expression levels are abnormally elevated in multiple neurological diseases, instructs presynaptic growth at the axonal terminals in C4da neurons. Dscam expression levels strongly correlate with presynaptic length; whereas loss or gain of Dscam does not elicit any changes in dendritic growth, suggesting that Dscam specifically controls axonal growth. In Chapter 5, I show that the Krüppel-like transcription factor Dar1, which promotes dendritic but not axonal growth, is a key factor determining the multipolar organization of neuronal dendrites. In summary, my thesis research has identified three intrinsic molecule mechanisms that differentially regulate dendritic and axonal growth, and provides novel paradigms for understanding the diversity of neuron morphology.

[发布机构] University of Michigan

[效力级别] Axonal Development

[关键词] Dendritic Development;Axonal Development;Dual Leucine Zipper Kinase (DLK);Down Syndrome Cell Adhesion Molecule (Dscam);KrüPpel-like Transcription Factor Dar1;Synaptic Growth;Molecular;Cellular and Developmental Biology;Science;Molecular, Cellular and Developmental Biology