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The unfolded protein response regulator ATF6 promotes mesodermal differentiation.
Heike Kroeger1, Neil Grimsey2, Ryan Paxman3
1Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
Science Signaling
|February 15, 2018
Summary
Activating transcription factor 6 (ATF6) suppresses stem cell pluripotency and promotes differentiation. Modulating ATF6 offers a novel strategy for generating mesodermal tissues.
Area of Science:
- Cell Biology
- Developmental Biology
- Molecular Biology
Background:
- Activating transcription factor 6 (ATF6) is an endoplasmic reticulum (ER)-resident transcription factor activated during the unfolded protein response (UPR).
- Loss of ATF6 function in vertebrates causes embryonic lethality and developmental defects, suggesting a critical role in development.
- Mutations in ATF6α are linked to human congenital vision loss, further highlighting its developmental importance.
Purpose of the Study:
- To investigate the role of ATF6 in human stem cell differentiation.
- To explore ATF6's potential in directing cell fate during early development.
- To identify novel strategies for generating specific tissue types from stem cells.
Main Methods:
- Human stem cells were differentiated into various cell types.
- ATF6 activity was manipulated using a small-molecule agonist and patient-derived induced pluripotent stem cells with ATF6 mutations.
- Cell fate and differentiation markers were analyzed.
Main Results:
- ATF6 activation suppressed pluripotency markers in stem cells.
- ATF6 promoted stem cell differentiation into various cell lineages.
- Specifically, ATF6 directed cell fate towards the mesodermal lineage.
- Inhibition of ATF6 using patient-derived cells confirmed its role in differentiation.
Conclusions:
- ATF6 plays a crucial role in suppressing pluripotency and promoting differentiation during stem cell development.
- Modulating ATF6 activity represents a promising new strategy for the targeted generation of mesodermal tissues.
- This research provides insights into the developmental functions of the ATF6 pathway in the UPR.
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