Dendrite Morphogenesis and Channel Regulation: Implications for Mental Health and Neurological Disorders
Lily Jan, University of California, San Francisco; Yuh"Nung Jan, University of California, San Francisco
Description: Lily and Yuh"Nung Jan have been pioneers in the field of molecular neurobiology for more than 30 years, and their genetic studies of fruit flies and mice have provided major insights into many different aspects of brain function and development. In this joint lecture, they summarize their recent work on the genetic control of neuronal shape and of electrical properties, including many implications for human brain disorders.
The brain's extraordinary wiring complexity is largely due to dendrites, the elaborate branched structures through which neurons receive incoming signals. In the first part of their joint lecture, Yuh"Nung Jan summarizes the genetic mechanisms that control the shapes of these elaborate structures.
Jan describes how dendrites recognize and avoid other dendrites of the same neuron, while ignoring dendrites from adjacent neurons. The key to this self/non"self discrimination ability is a remarkable gene called dsCAM, which encodes some 38,000 different splice variants. Each neuron is believed to express a different subset of these variants, giving it a unique molecular identity. Genetic studies are also starting to reveal how dendritic arbor size is regulated. Like a well" pruned tree, dendritic arbors are dynamic structures in which new growth and branch removal are kept in precise balance. Jan estimates that around 100 genes are involved in this process, and he argues that mutations in these genes could contribute significantly to many human brain disorders.
Studies of dendritic structure are providing insights into neurodegenerative diseases such as Huntington's disease. Jan shows that over"expression of the human mutant protein in fruit fly neurons causes systematic changes to their dendrites, making these flies an ideal system in which to study the disease mechanism and identify new therapeutic strategies.
The Jans have been pioneers in the study of potassium channels (K channels), the most abundant class of ion channels in the brain. In the second part of their joint presentation, Lily Jan examines the complex regulatory mechanisms by which K channels regulate brain's activity.
To function properly, K channels must be targeted to the correct part of the neuron. Jan describes how this is accomplished for a prototypical mouse K channel known as Kv1, with the help of two associated proteins that are responsible for transporting the channel molecules along axons.
Kv1 is also present in dendrites but it gets there via a different mechanism. Rather than transporting the protein, as happens in axons, the RNA encoding the channel is localized to dendrites, where its translation is controlled locally by electrical activity at synaptic sites. Jan describes the pathway by which this happens, which appears to constitute a positive feedback loop _ synaptic activity suppresses the synthesis of Kv1.1, thus increasing activity levels still further. She then shows how disruptions to this feedback pathway could contribute to autism and pervasive developmental disorder.
In the final part of the talk, Jan describes the regulation of another class of K channels known as GIRKs. Unlike the voltage"gated Kv channels, which open and close rapidly in response to electrical activity, the GIRK channels open more slowly (seconds rather than milliseconds) in response to chemical signals between neurons. GIRK channels were recently found to be concentrated at excitatory synapses within the brain, and Jan presents evidence that GIRK channels may play a fundamental role in controlling synaptic plasticity and learning.
About the Speaker(s): Lily Jan, PhD Jack and DeLoris Lange Professor of Physiology and Biophysics at the University of California, San Francisco Howard Hughes Medical Institute Investigator Lily Jan studies the function and regulation of potassium channels and calcium"activated chloride channels in the brain. Jan earned her B.Sc. in Physics from National Taiwan University in 1968 and her M.Sc. in Physics from the California Institute of Technology in 1970. Lily married Yuh Nung Jan in 1971, when they were graduate students at CalTech, and have shared a laboratory since 1979. After beginning their PhD studies at Caltech set on careers in theoretical physics, they both chose to switch careers and follow their interest in biology. Their first significant discovery was to prove the existence of peptide neurotransmitters. Since then, the Jans have been pioneers in the study of potassium channels, which are central to understanding the brain's electrical properties, and they have become leaders in the field of developmental neuroscience. http://www.hhmi.org/research/investigators/janly_bio.html http://physio.ucsf.edu/jan/ Yuh"Nung Jan, PhD Jack and DeLoris Lange Professor of Molecular Physiology at the University of California, San Francisco Howard Hughes Medical Institute Investigator Yuh"Nung Jan is interested in the basic mechanisms that control diversity of neuronal morphology, dendrite development, and neuronal circuitry formation. Using the relatively simple nervous system of Drosophila as a model, Yuh Nung hopes to discover the genetic program that controls its development and uncover evolutionarily conserved core programs that control neural development in animals. Jan earned his B.Sc. in Physics from National Taiwan University in 1967 and went on to earn his M.Sc. in Physics from California Institute of Technology in 1970. Yuh"Nung married Lily Jan in 1971, when they were graduate students at CalTech, and have shared a laboratory since 1979. After beginning their PhD studies at Caltech set on careers in theoretical physics, they both chose to switch careers and follow their interest in biology. Their first significant discovery was to prove the existence of peptide neurotransmitters. Since then, the Jans have been pioneers in the study of potassium channels, which are central to understanding the brain's electrical properties, and they have become leaders in the field of developmental neuroscience. http://physio.ucsf.edu/jan/ http://www.hhmi.org/research/investigators/janyn_bio.html
Host(s): School of Science, McGovern Institute for Brain Research at MIT
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