Schizophrenia Research Forum - A Catalyst for Creative Thinking
Home Profile Membership/Get Newsletter Log In Contact Us
 For Patients & Families
What's New
Recent Updates
SRF Papers
Current Papers
Search All Papers
Search Comments
Research News
Conference News
Plain English
Current Hypotheses
Idea Lab
Online Discussions
Virtual Conferences
What We Know
Animal Models
Drugs in Trials
Research Tools
Community Calendar
General Information
Member Directory
Researcher Profiles
Institutes and Labs
About the Site
SRF Team
Advisory Board
Support Us
How to Cite
Fan (E)Mail
The Schizophrenia Research Forum web site is sponsored by the Brain and Behavior Research Foundation and was created with funding from the U.S. National Institute of Mental Health.
Research News
back to News Search Plain English
ANK3 Regulates Neuron Proliferation

June 13, 2014. Ankyrin-G, the protein product of the gene ANK3 that has been linked to bipolar disorder and schizophrenia, has a hand in regulating the birth of new neurons in the developing brain. So says a study published online May 13 in Molecular Psychiatry, led by Li-Huei Tsai of the Massachusetts Institute of Technology, in Cambridge. The study reports that loss of ANK3 resulted in a relocation of β-catenin to the nucleus, where it promoted neural proliferation in mouse embryonic neurons. This proliferation could be pulled back to normal levels, however, by degrading β-catenin with the enzyme glycogen synthase kinase 3 (GSK3β). This suggests that bipolar disorder stems from disruptions to brain development – already a prominent theme for schizophrenia.

The study marks a step toward figuring out the function of the genes filtering in from genetic studies of psychiatric illnesses. ANK3 has been fingered in studies of common and rare variants alike for both schizophrenia and bipolar disorder (see SRF related news report). Moreover, a postmortem study has found abnormalities in ANK3 transcription in schizophrenia (see SRF related news report). ANK3 encodes the scaffolding protein ankyrin-G, which helps hold in place the voltage-gated channels at the axon’s initial segment and nodes of Ranvier – regions critical to action potential propagation. ANK3 is also thought to be important for establishing cell orientation—which part of a neuron is up and which is down.

The new study draws ANK3 into the sphere of influence of the Wnt pathway, which transduces signals from the outside of the cell to trigger transcription inside the nucleus. The Wnt pathway regulates neural proliferation, dendrite formation, and synapse construction in the developing brain. Tsai’s lab previously found that schizophrenia-related variants in Disrupted-in-Schizophrenia-1 (DISC1) decreased neural proliferation through the Wnt pathway (see SRF related news report), while the new study finds that ANK3 loss leads to increased proliferation.

β-catenin supply
First authors Omer Durak and Froylan Calderon de Anda first noted particularly high levels of ankyrin-G in the ventricular zone, a birthplace for cortical neurons, in embryonic mouse brain. This suggested it may be involved in neural proliferation, and knockdown of ANK3 in these brains using short-hairpin (sh) RNA resulted in a significant increase in newborn neurons two or 24 hours later, compared to those receiving a control shRNA. Similarly, mice lacking one copy of ANK3 also showed signs of increased neural proliferation.

Next, the researchers checked to see if ANK3 knockdown revved up Wnt signaling, given its involvement in neural proliferation, and found that it did: Following ANK3 knockdown, neurons from postnatal day 19 mice kept in culture showed increased levels of TCF/LEF transcription, a sign of Wnt signaling.

ANK3 knockdown did not change the amounts of the different Wnt signaling members, however. Instead, it shifted the localization of β-catenin, a core member of the Wnt pathway. Typically β-catenin binds to E-cadherin, an adhesion protein, and the complex is concentrated along the cell membrane. After ANK3 knockdown, this was less pronounced, and an increase in β-catenin signal emanating from the nucleus also emerged.

The researchers propose that ANK3 knockdown somehow frees β-catenin from E-cadherin, thus increasing the supply of free β-catenin available to enter the nucleus. This suggests that ANK3 levels could fine-tune Wnt signaling. Consistent with this, degrading β-catenin by overexpressing GSK3β, an enzyme that tags β -catenin for removal, reversed ANK3 knockdown’s effects, producing normal levels of neural proliferation.

Knockdown of ANK3 in mice results in behavioral abnormalities (Leussis et al., 2013), and the new results suggest that disruptions to Wnt signaling might contribute to these. Though whether ANK3 variants implicated in bipolar or schizophrenia turn down ANK3 expression remains unclear, the results bolster the role for the Wnt pathway in the neurodevelopment, and argue for paying close attention to the subcellular locations of interesting molecules.—Michele Solis.

Durak O, de Anda FC, Singh KK, Leussis MP, Petryshen TL, Sklar P, Tsai LH. Ankyrin-G regulates neurogenesis and Wnt signaling by altering the subcellular localization of β-catenin. Mol Psychiatry. 2014 May 13. Abstract

Submit a Comment on this News Article
Make a comment on this news article. 

If you already are a member, please login.
Not sure if you are a member? Search our member database.

*First Name  
*Last Name  
Country or Territory  
*Login Email Address  
*Confirm Email Address  
*Confirm Password  
Remember my Login and Password?  
Get SRF newsletter with recent commentary?  
Enter the code as it is shown below:
This code helps prevent automated registrations.

I recommend the Primary Papers

Please note: A member needs to be both registered and logged in to submit a comment.


(If coauthors exist for this comment, please enter their names and email addresses at the end of the comment.)


SRF News
SRF Comments
Text Size
Reset Text Size
Copyright © 2005- 2016 Schizophrenia Research Forum Privacy Policy Disclaimer Disclosure Copyright