October 9 - 12, 2012
Building 10 & Natcher Conference Center
- General Schedule of Events
- Opening Plenary Session
- Concurrent Symposia Sessions
- Poster Sessions
- National Graduate Student Research Conference
- FARE Award Ceremony
- Special Exhibits on Resources for Intramural Research
- TSA Research Festival Exhibit Show
- Clinical Center Tours
- Research Festival Committees
- Past Research Festivals
Role for cholesterol/Wnt interactions in balancing pluripotency and neural differentiation
| Friday, November 08, 2013 — Poster Session III | |||
|---|---|---|---|
10:00 a.m. – 12:00 p.m. |
FAES Academic Center (Upper-Level Terrace) |
NICHD |
STEMCELL-6 |
Authors
- K.R. Francis
- A.N Ton
- C.A. Wassif
- H.J. Westphal
- F.D. Porter
Abstract
Identifying mechanisms that regulate pluripotency versus neural differentiation are important for understanding development and neurological disease. While cholesterol regulates many cellular functions, its effects on the balance between pluripotency and differentiation are unclear. Smith-Lemli-Opitz Syndrome (SLOS) is caused by mutations in 7-dehydrocholesterol reductase, limiting cholesterol synthesis and causing neurological dysfunction. We generated and characterized induced pluripotent stem cells (iPSCs) from SLOS patients, finding no differences between patient and control lines when cultured in high cholesterol. A hallmark of SLOS is the accumulation of 7,8-dehydrocholesterols (DHCs) and reduced cholesterol content. While controls never accumulate DHCs, culture of SLOS iPSCs in cholesterol free media revealed a time-dependent increase in DHCs and decrease in cholesterol. Neural differentiation assays revealed SLOS cells matured from neural progenitors to differentiated neurons and glia ~300% faster than controls. Further, pluripotent SLOS iPSCs spontaneously formed CNS (Pax6+) and PNS (Sox10+) progenitors in cholesterol free conditions. Small molecule mimetics of SLOS also induced similar effects on control iPSCs. A subsequent microarray time-course identified loss of Wnt/beta-catenin signaling as a key initiator of differentiation, where inhibition of GSK3-beta prevented both beta-catenin degradation and SLOS differentiation. This work identifies a novel role for cholesterol/Wnt interactions in balancing pluripotency and neural differentiation.
