Helen Willsey, PhD

Asst Professor in Residence
Psychiatry
[email protected]

The Willsey Lab uses the powerful Xenopus tropicalis (diploid frog) model to translate success in psychiatric disorder genetics into actionable mechanisms of risk and resilience. Our work to date has focused on high-confidence, large-effect risk genes for Autism Spectrum Disorders (ASD), where we have identified a convergent phenotype during forebrain neurogenesis. Specifically, we created half-mutant animals (divided by the midline) by CRISPR/Cas9 targeted injections and observed defects in neural progenitor maturation for the top 10 ASD risk genes. By drug screening, we identified estrogen signaling as a potential resilience factor for multiple different genes. Going forward, we are focusing on how these risk genes affect neurogenesis, how estrogen signaling interacts, and expanding this experimental platform to begin work on other disorders with large-effect risk genes, including Schizophrenia, Tourette Disorder, ADHD, and OCD.

Research Summary: 
We use Xenopus tropicalis, diploid frogs, as a high-throughput platform for genetic analysis to identify convergent biology underlying psychiatric disorder risk genes
Publications: 

Ciliary biology intersects autism and congenital heart disease.

bioRxiv : the preprint server for biology

Teerikorpi N, Lasser MC, Wang S, Kostyanovskaya E, Bader E, Sun N, Dea J, Nowakowski TJ, Willsey AJ, Willsey HR

Autism gene variants disrupt enteric neuron migration and cause gastrointestinal dysmotility.

bioRxiv : the preprint server for biology

McCluskey KE, Stovell KM, Law K, Kostyanovskaya E, Schmidt J, Exner CRT, Dea J, Brimble E, State MW, Willsey AJ, Willsey HR

Modelling human genetic disorders in Xenopus tropicalis.

Disease models & mechanisms

Willsey HR, Seaby EG, Godwin A, Ennis S, Guille M, Grainger RM

A foundational atlas of autism protein interactions reveals molecular convergence.

bioRxiv : the preprint server for biology

Wang B, Vartak R, Zaltsman Y, Naing ZZC, Hennick KM, Polacco BJ, Bashir A, Eckhardt M, Bouhaddou M, Xu J, Sun N, Lasser MC, Zhou Y, McKetney J, Guiley KZ, Chan U, Kaye JA, Chadha N, Cakir M, Gordon M, Khare P, Drake S, Drury V, Burke DF, Gonzalez S, Alkhairy S, Thomas R, Lam S, Morris M, Bader E, Seyler M, Baum T, Krasnoff R, Wang S, Pham P, Arbalaez J, Pratt D, Chag S, Mahmood N, Rolland T, Bourgeron T, Finkbeiner S, Swaney DL, Bandyopadhay S, Ideker T, Beltrao P, Willsey HR, Obernier K, Nowakowski TJ, Hüttenhain R, State MW, Willsey AJ, Krogan NJ

Autism genes converge on microtubule biology and RNA-binding proteins during excitatory neurogenesis.

bioRxiv : the preprint server for biology

Sun N, Teyssier N, Wang B, Drake S, Seyler M, Zaltsman Y, Everitt A, Teerikorpi N, Willsey HR, Goodarzi H, Tian R, Kampmann M, Willsey AJ

Pleiotropy of autism-associated chromatin regulators.

Development (Cambridge, England)

Lasser M, Sun N, Xu Y, Wang S, Drake S, Law K, Gonzalez S, Wang B, Drury V, Castillo O, Zaltsman Y, Dea J, Bader E, McCluskey KE, State MW, Willsey AJ, Willsey HR

Genomics, convergent neuroscience and progress in understanding autism spectrum disorder.

Nature reviews. Neuroscience

Willsey HR, Willsey AJ, Wang B, State MW

Modeling Human Genetic Disorders with CRISPR Technologies in Xenopus.

Cold Spring Harbor protocols

Willsey HR, Guille M, Grainger RM

Picroscope: low-cost system for simultaneous longitudinal biological imaging.

Communications biology

Ly VT, Baudin PV, Pansodtee P, Jung EA, Voitiuk K, Rosen YM, Willsey HR, Mantalas GL, Seiler ST, Selberg JA, Cordero SA, Ross JM, Rolandi M, Pollen AA, Nowakowski TJ, Haussler D, Mostajo-Radji MA, Salama SR, Teodorescu M

Deep learning is widely applicable to phenotyping embryonic development and disease.

Development (Cambridge, England)

Naert T, Çiçek Ö, Ogar P, Bürgi M, Shaidani NI, Kaminski MM, Xu Y, Grand K, Vujanovic M, Prata D, Hildebrandt F, Brox T, Ronneberger O, Voigt FF, Helmchen F, Loffing J, Horb ME, Willsey HR, Lienkamp SS

A convergent molecular network underlying autism and congenital heart disease.

Cell systems

Rosenthal SB, Willsey HR, Xu Y, Mei Y, Dea J, Wang S, Curtis C, Sempou E, Khokha MK, Chi NC, Willsey AJ, Fisch KM, Ideker T

Parallel in vivo analysis of large-effect autism genes implicates cortical neurogenesis and estrogen in risk and resilience.

Neuron

Willsey HR, Exner CRT, Xu Y, Everitt A, Sun N, Wang B, Dea J, Schmunk G, Zaltsman Y, Teerikorpi N, Kim A, Anderson AS, Shin D, Seyler M, Nowakowski TJ, Harland RM, Willsey AJ, State MW

Xenopus leads the way: Frogs as a pioneering model to understand the human brain.

Genesis (New York, N.Y. : 2000)

Exner CRT, Willsey HR

In Xenopus ependymal cilia drive embryonic CSF circulation and brain development independently of cardiac pulsatile forces.

Fluids and barriers of the CNS

Dur AH, Tang T, Viviano S, Sekuri A, Willsey HR, Tagare HD, Kahle KT, Deniz E

The neurodevelopmental disorder risk gene DYRK1A is required for ciliogenesis and control of brain size in Xenopus embryos.

Development (Cambridge, England)

Willsey HR, Xu Y, Everitt A, Dea J, Exner CRT, Willsey AJ, State MW, Harland RM

DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract.

Genetics in medicine : official journal of the American College of Medical Genetics

Blackburn ATM, Bekheirnia N, Uma VC, Corkins ME, Xu Y, Rosenfeld JA, Bainbridge MN, Yang Y, Liu P, Madan-Khetarpal S, Delgado MR, Hudgins L, Krantz I, Rodriguez-Buritica D, Wheeler PG, Al-Gazali L, Mohamed Saeed Mohamed Al Shamsi A, Gomez-Ospina N, Chao HT, Mirzaa GM, Scheuerle AE, Kukolich MK, Scaglia F, Eng C, Willsey HR, Braun MC, Lamb DJ, Miller RK, Bekheirnia MR

Katanin-like protein Katnal2 is required for ciliogenesis and brain development in Xenopus embryos.

Developmental biology

Willsey HR, Walentek P, Exner CRT, Xu Y, Lane AB, Harland RM, Heald R, Santama N

The Psychiatric Cell Map Initiative: A Convergent Systems Biological Approach to Illuminating Key Molecular Pathways in Neuropsychiatric Disorders.

Cell

Willsey AJ, Morris MT, Wang S, Willsey HR, Sun N, Teerikorpi N, Baum TB, Cagney G, Bender KJ, Desai TA, Srivastava D, Davis GW, Doudna J, Chang E, Sohal V, Lowenstein DH, Li H, Agard D, Keiser MJ, Shoichet B, von Zastrow M, Mucke L, Finkbeiner S, Gan L, Sestan N, Ward ME, Huttenhain R, Nowakowski TJ, Bellen HJ, Frank LM, Khokha MK, Lifton RP, Kampmann M, Ideker T, State MW, Krogan NJ

Localized JNK signaling regulates organ size during development.

eLife

Willsey HR, Zheng X, Carlos Pastor-Pareja J, Willsey AJ, Beachy PA, Xu T

Gp93, the Drosophila GRP94 ortholog, is required for gut epithelial homeostasis and nutrient assimilation-coupled growth control.

Developmental biology

Maynard JC, Pham T, Zheng T, Jockheck-Clark A, Rankin HB, Newgard CB, Spana EP, Nicchitta CV