Assistant Professor of Neurobiology
Drosophila Models of Human Disease, Microcephaly, Mechanisms of Virus-Induced Disease, Neuronal Stem Cells, Neurodevelopment
We are interested in the diagnosis and study of neurological diseases. We focus on microcephaly, a devasting neurodevelopmental condition that affects brain development and is characterized by reduced brain size. What genes are associated with microcephaly, do they belong to essential pathways that govern brain size, and what are the molecular mechanisms of these pathways during neuronal development and disease?
ANKLE2 is part of a conserved neurodevelopmental pathway associated with disease
We identified a family with variants in ANKLE2 with severe primary microcephaly. Drosophila Ankle2 mutants also have reduced brain volume that can be rescued by expression of wild type, but not disease variant, human ANKLE2. These findings indicate conserved functions of ANKLE2, provide compelling evidence that loss of ANKLE2 causes microcephaly, and establish proof of principle that we can study the pathogenesis of disease with this humanized fly system. Ankle2 interacts with the kinase Ballchen, the homolog of VRK1, to regulate asymmetric division of stem cells, a critical process for cell fate specification and the development of neurons. We are currently investigating cellular mechanisms by which Ankle2 acts in neuronal stem cells and the developing nervous system.
A Zika virus protein, NS4A, inhibits ANKLE2 to cause microcephaly
Zika virus infection is also associated with severe microcephaly, and we identified that a Zika virus protein, NS4A, interacts with and inhibits ANKLE2 function. Expression of NS4A in Drosophila results in small brains, while overexpression of human ANKLE2 reverses these phenotypes. These data provide a compelling explanation for how Zika virus induces microcephaly while highlighting potential therapeutic targets. We are currently investigating how NS4A inhibits Ankle2 function and whether this interaction is conserved.
An in vivo platform to functionally interrogate clinically implicated variants
We have established a pipeline to investigate novel causes of microcephaly using a human centric approach. To identify variants that might be associated with disease, patients with unknown causes of microcephaly were evaluated using exome sequencing. Using Drosophila, we assess the function of variants associated with microcephaly to: 1) promote diagnoses for patients and identify novel genes associated with the disease, 2) illuminate essential pathways for normal brain development, 3) provide a model to elucidate mechanisms of development and disease, and 4) in some instances, enable development of therapeutics.
- Link N, Chung H, Jolly A, Withers M, Tepe B, Arenkiel BR, Shah PS, Krogan NJ, Aydin H, Geckinli BB, Tos T, Isikay S, Tuysuz B, Mochida GH, Thomas AX, Clark RD, Mirzaa GM, Lupski JR, Bellen HJ (2019). Mutations in ANKLE2, a ZIKA Virus Target, Disrupt an Asymmetric Cell Division Pathway in Drosophila Neuroblasts to Cause Dev Cell, 51(6), 713-729.e6.
- Shah PS, Link N, Jang GM, Sharp PP, Zhu T, Swaney DL, Johnson JR, Von Dollen J, Ramage HR, Satkamp L, Newton B, Hüttenhain R, Petit MJ, Baum T, Everitt A, Laufman O, Tassetto M, Shales M, Stevenson E, Iglesias GN, Shokat L, Tripathi S, Balasubramaniam V, Webb LG, Aguirre S, Willsey AJ, Garcia-Sastre A, Pollard KS, Cherry S, Gamarnik AV, Marazzi I, Taunton J, Fernandez-Sesma A, Bellen HJ, Andino R, Krogan NJ (2018). Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis. Cell, 175(7), 1931-1945.e18.
- Yamamoto S, Jaiswal M, Charng WL, Gambin T, Karaca E, Mirzaa G, Wiszniewski W, Sandoval H, Haelterman NA, Xiong B, Zhang K, Bayat V, David G, Li T, Chen K, Gala U, Harel T, Pehlivan D, Penney S, Vissers LELM, de Ligt J, Jhangiani SN, Xie Y, Tsang SH, Parman Y, Sivaci M, Battaloglu E, Muzny D, Wan YW, Liu Z, Lin-Moore AT, Clark RD, Curry CJ, Link N, Schulze KL, Boerwinkle E, Dobyns WB, Allikmets R, Gibbs RA, Chen R, Lupski JR, Wangler MF, Bellen HJ (2014). A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases. Cell, 159(1), 200-214.