The formation of the primitive streak (PS) and the subsequent induction of neuroectoderm are hallmarks of gastrulation. Combining an in vitro reconstitution of this process based on mouse embryonic stem cells (mESCs) with a collection of knockouts in reporter mESC lines, we identified retinoic acid (RA) as a critical mediator of early neural induction triggered by TGFβ or Wnt signaling inhibition. Single-cell RNA sequencing analysis captured the temporal unfolding of cell type diversification, up to the emergence of somite and neural fates. In the absence of the RA-synthesizing enzyme Aldh1a2, a sensitive RA reporter revealed a hitherto unidentified residual RA signaling that specified neural fate. Genetic evidence showed that the RA-degrading enzyme Cyp26a1 protected PS-like cells from neural induction, even in the absence of TGFβ and Wnt antagonists. Overall, we characterized a multi-layered control of RA levels that regulates early neural differentiation in an in vitro PS-like system.
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http://dx.doi.org/10.1016/j.stemcr.2021.12.014 | DOI Listing |
Angew Chem Int Ed Engl
January 2025
University of Chicago Division of the Physical Sciences, chemistry, UNITED STATES OF AMERICA.
Immune checkpoint blockade (ICB) has revolutionized the treatment of many cancers by leveraging the immune system to combat malignancies. However, its efficacy is limited by the immunosuppressive tumor microenvironment and other regulatory mechanisms of the immune system. Innate immune modulators (IIMs) provide potent immune activation to complement adaptive immune responses and help overcome resistance to ICB.
View Article and Find Full Text PDFBackground: In Alzheimer's disease (AD), histone acetylation is disrupted, suggesting loss of transcriptional control. Moreover, converging evidence suggests an age- and AD-dependent loss of transcription controlled by all-trans-retinoic acid (ATRA), the bioactive metabolite of vitamin A (VA). Antioxidant depletion causes oxidative stress (OS).
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Texas Tech University Health Sciences Center, Lubbock, TX, USA.
Background: Disrupted balance between amyloidogenic and non-amyloidogenic pathways leads to cognitive decline in Alzheimer's disease (AD). Evidence suggests vitamin A (VA) supplementation favors the non-amyloidogenic pathway through upregulation of α-secretase. Originally used to map embryonic retinoic acid (RA) signaling, RARE-LacZ mice possess multiple LacZ genes controlled by retinoic acid response elements (RAREs).
View Article and Find Full Text PDFInt J Biol Sci
January 2025
Department of Otolaryngology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138, Sheng Li Road, Tainan, Taiwan, 70456.
Results of retinoid-based therapies in head and neck cancer (HNC) are generally disappointing, indicating a lack of understanding of retinoic acid signaling. The role of retinoic acid receptor gamma (RARγ) and its isoforms in HNC is yet to be established. In this study, we found that RARγ1, 2, 4 are the predominant RARγ isoforms expressed in various types of human cancers, including HNC.
View Article and Find Full Text PDFInt J Biol Macromol
December 2024
Department of Veterinary Medicine, College of Animal Science and Technology, Hebei North University, Zhangjiakou, Hebei 075131, China. Electronic address:
Osteoporosis (OP) is a significant global public health concern that requires the development of safe and effective drugs for prevention and treatment. Sugemule-7 (SGML-7) decoction, a traditional Mongolian herbal prescription, has long been used for treating OP, but its components and mechanisms of action remain unclear. The study identified the main compounds of SGML-7 using UHPLC-Q Exactive MS and explored the multi-target mechanisms of SGML-7 in OP through network pharmacology and molecular docking.
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