Feng, Yuanyi, PhD

Information

Name

Feng, Yuanyi, PhD

Title

Assistant Professor

Email

yuanyi-feng@northwestern.edu

Office Phone

312-503-1046

Department

Neurology

Office

Lurie 7-111 Chicago

Areas of Research

Cell Biology, Molecular Neuroscience, Neurobiology of Disease, Signal Transduction

NU Scholar Profile

http://www.scholars.northwestern.edu/expert.asp?u_id=665

Recent Publications on PubMed

http://www.ncbi.nlm.nih.gov/pubmed?term=Feng%2C%20Yuanyi%5BFull%20Author%20Name%5D&cmd=DetailsSearch

Current Research

Current Research

We are interested in fundamental mechanisms controlling development of the cerebral cortex.

As the structure responsible for intellectual activities, the cerebral cortex in human is composed of a sheet of approximately 10 billion neurons organized in 6 layers. The logarithmic expansion of the neuronal population from dividing progenitors results in an excessively convoluted structure with gyri and sulci (referring the ridges and grooves on brain surface, respectively). The highly ordered cortical neuronal arrays develop through tightly regulated steps of neurogenesis, neuronal migration and differentiation.

To understand molecular mechanisms underlying cerebral cortical development, we study genes of which mutations cause abnormal formation of the cerebral cortex.

Classical lissencephaly (smooth brain) is one of the most severe forms of cortical malformation disorders, and can be caused by heterozygous mutations of LIS1 . LIS1 is a ubiquitously expressed cytoplasmic molecule that functions by interacting with other cellular proteins. One of the proteins that LIS1 binds is Nde1, a centrosomal scaffold essential for microtubule organization and mitotic spindle function. Blocking LIS1-Nde1 interaction in Xenopus embryos results in severe lamination defects in retina and brain, and the homozygous mutation of Nde1 in mice produces a specific size reduction of the cerebral cortex. Nde1 is highly expressed in the cerebral cortical neural progenitor cells. Mutation of Nde1 leads to severe cortical progenitor cell division defects, resulting in reduced self renewal and increased neurogenesis of cortical progenitors, early depletion of progenitor pool and ablation of later-born superficial layer II/III neurons in the cerebral cortex. Many of the mitotic defects presented by Nde1 mutants were also seen in Lis1 mutant mice, suggesting that Nde1 functions together with Lis1 in neural progenitor cells. Lis1-Nde1 double mutant mice are currently being analyzed to address the functional relationship of the two genes in cortical development. Mutations in both Lis1 and Nde1 also result in retarded neuronal migration, the molecular mechanism underlying Lis1 and Nde1's role in cortical neuronal migration is also under current investigation.

A. Images of a normal and a lissencephalic brain. Heterozygous mutations of LIS1 may result in severe reduction or complete absence of cerebral cortical gyri and sulci, profound mental retardation, intractable epilepsy and early postnatal death.

B. MRI images of a normal and a "PH" brain due to FLNA mutation. Note the presence of neuronal nodules along the lateral ventricle (red arrows).

Periventricular Heterotopia (PH) is another example of cerebral cortical malformations in which ectopic neurons are present near the brain ventricle, deep beneath their normal location in the cerebral cortex. PH is often an X-linked disease occurring predominantly in females with seizures, whereas males in affected families usually die prenatally of hemorrhage and multiple organ failures. Mutations in the FLNA are found in most of the PH cases. FLNA is a widely studied actin binding protein, and was initially purified through its actin cross-linking activities. FLNA has also been shown to interact with over 30 proteins with diverse cellular functions. As many of the FLNA interactors are cell signaling molecules, FLNA may be important for linking various cell signaling pathways to the actin cytoskeleton. In order to understand the role of FLNA in cerebral cortex development and to dissect FLNA mediated signaling pathways, we have generated Flna knockout and conditional knockout mice and analyzed their developmental defects. Current studies have suggested that FLNA acts downstream of multiple receptors and is required for the normal function of cerebral cortical neural progenitor cells, neural crest cells and vascular endothelial cells in both brain and cardiovascular development. Further studies with combined cell biology and mouse genetics will allow a better understanding of the molecular mechanism of FLNA in cortical development as well as the pathogenic basis of PH and other developmental defects seen in patients with FLNA mutations.