Fen-Biao Gao, Ph.D.
Associate Investigator
Gladstone Institute of Neurological Disease
Associate Professor of Neurology
University of California, San Francisco
Email: fgao@gladstone.ucsf.edu
Telephone: 415-734-2514
Fax: 415-355-0230

Areas of Investigation
Our laboratory focuses on two lines of investigation. One is to understand the pathogenesis of frontotemporal dementia (FTD) and to identify new targets for therapeutic interventions. The second is to study the molecular mechanisms underlying neuronal development, with an emphasis on microRNAs and a few neurodevelopmental disorders, including fragile X syndrome.

Significance
During the last decade, enormous progress has been made in understanding neural development. Although many mysteries remain, it is exciting to know that by deciphering how the brain is built, we can help to unravel the molecular and cellular bases of many neurological disorders. Conversely, studies on diseases are offering new insights into normal developmental processes. Studies in different model systems will undoubtedly lead to new therapeutic interventions for many seemingly intractable neurological diseases.

Approaches
We use a combination of behavioral, genetic, molecular, cellular, biochemical, and imaging approaches to understand both neurodevelopmental and neurodegenerative diseases. We take advantage of both fly and mouse genetics, as well as in vitro cell culture systems.

Contributions
Neurons distinguish themselves from other cell types partly by their size and shape, especially their unique and often highly branched dendritic trees, which remain relatively stable for decades. Over the years, we have identified and/or characterized several key players that control different aspects of dendritic morphogenesis, including the fly homolog of human fragile X mental retardation protein 1 (dFMR1). dFMR1 is associated with the microRNA pathway. More recently, we demonstrated that microRNA-9a plays a unique role in ensuring the precision of gene expression during neuronal development (Li et al., Genes Dev. 2006). Moreover, we cloned shrub, a novel fly gene encoding an essential component of the endosomal sorting complex required for transport (ESCRT-III) (Sweeney et al., Curr. Biol. 2006). We showed that Shrub and its mammalian homolog, mSnf7-2, affect dendritic morphogenesis. We also showed that ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration either through loss of mSnf7-2 or expression of CHMP2BIntron5, an FTD-associated mutant protein (Lee et al., Curr. Biol. 2007). These findings may have important implications for understanding FTD and other age-dependent neurodegenerative diseases.

Some Questions Addressed in Ongoing Studies

• How does dysfunctional ESCRT-III cause neurodegeneration and what are the implications for our understanding of FTD?

• How does the microRNA pathway modulate neuronal development and contribute to neurodevelopmental disorders?