SAFB Regulates Hippocampal Stem Cell Fate by Targeting Drosha to Destabilize MRNA

Overview

Journal Elife

Specialty Biology

Date 2024 May 9

PMID 38722021

Authors

Pascal Forcella

Niklas Ifflander

Chiara Rolando

Elli-Anna Balta

Aikaterini Lampada

Claudio Giachino

Tanzila Mukhtar

Thomas Bock

Verdon Taylor

Affiliations

Soon will be listed here.

Abstract

Neural stem cells (NSCs) are multipotent and correct fate determination is crucial to guarantee brain formation and homeostasis. How NSCs are instructed to generate neuronal or glial progeny is not well understood. Here, we addressed how murine adult hippocampal NSC fate is regulated and described how scaffold attachment factor B (SAFB) blocks oligodendrocyte production to enable neuron generation. We found that SAFB prevents NSC expression of the transcription factor nuclear factor I/B (NFIB) by binding to sequences in the mRNA and enhancing Drosha-dependent cleavage of the transcripts. We show that increasing SAFB expression prevents oligodendrocyte production by multipotent adult NSCs, and conditional deletion of increases NFIB expression and oligodendrocyte formation in the adult hippocampus. Our results provide novel insights into a mechanism that controls Drosha functions for selective regulation of NSC fate by modulating the post-transcriptional destabilization of mRNA in a lineage-specific manner.

Citing Articles

Multimodal insights into adult neurogenesis: An integrative review of multi-omics approaches.

Li J, Huang L, Xiao W, Kong J, Hu M, Pan A Heliyon. 2025; 11(4):e42668.

PMID: 40051854 PMC: 11883395. DOI: 10.1016/j.heliyon.2025.e42668.

SAFB regulates hippocampal stem cell fate by targeting Drosha to destabilize mRNA.

Forcella P, Ifflander N, Rolando C, Balta E, Lampada A, Giachino C Elife. 2024; 13.

PMID: 38722021 PMC: 11149935. DOI: 10.7554/eLife.74940.

References

Lin Q, Taylor S, Shalloway D . Specificity and determinants of Sam68 RNA binding. Implications for the biological function of K homology domains. J Biol Chem. 1997; 272(43):27274-80. DOI: 10.1074/jbc.272.43.27274. View

Sergeant K, Bourgeois C, Dalgliesh C, Venables J, Stevenin J, Elliott D . Alternative RNA splicing complexes containing the scaffold attachment factor SAFB2. J Cell Sci. 2007; 120(Pt 2):309-19. DOI: 10.1242/jcs.03344. View

Obernier K, Alvarez-Buylla A . Neural stem cells: origin, heterogeneity and regulation in the adult mammalian brain. Development. 2019; 146(4). PMC: 6398449. DOI: 10.1242/dev.156059. View

Kim B, Jeong K, Kim V . Genome-wide Mapping of DROSHA Cleavage Sites on Primary MicroRNAs and Noncanonical Substrates. Mol Cell. 2017; 66(2):258-269.e5. DOI: 10.1016/j.molcel.2017.03.013. View

Chou C, Alexeeva O, Yamada S, Pribadi A, Zhang Y, Mo B . PABPN1 suppresses TDP-43 toxicity in ALS disease models. Hum Mol Genet. 2015; 24(18):5154-73. PMC: 4550816. DOI: 10.1093/hmg/ddv238. View

Shin Y, Berry J, Pannucci N, Haataja M, Toettcher J, Brangwynne C . Spatiotemporal Control of Intracellular Phase Transitions Using Light-Activated optoDroplets. Cell. 2017; 168(1-2):159-171.e14. PMC: 5562165. DOI: 10.1016/j.cell.2016.11.054. View

Macias S, Cordiner R, Gautier P, Plass M, Caceres J . DGCR8 Acts as an Adaptor for the Exosome Complex to Degrade Double-Stranded Structured RNAs. Mol Cell. 2015; 60(6):873-85. PMC: 4691244. DOI: 10.1016/j.molcel.2015.11.011. View

Townson S, Sullivan T, Zhang Q, Clark G, Osborne C, Lee A . HET/SAF-B overexpression causes growth arrest and multinuclearity and is associated with aneuploidy in human breast cancer. Clin Cancer Res. 2000; 6(9):3788-96. View

Matsuda T, Cepko C . Controlled expression of transgenes introduced by in vivo electroporation. Proc Natl Acad Sci U S A. 2007; 104(3):1027-32. PMC: 1764220. DOI: 10.1073/pnas.0610155104. View

10.

Treiber T, Treiber N, Plessmann U, Harlander S, Daiss J, Eichner N . A Compendium of RNA-Binding Proteins that Regulate MicroRNA Biogenesis. Mol Cell. 2017; 66(2):270-284.e13. DOI: 10.1016/j.molcel.2017.03.014. View

11.

Ahrne E, Glatter T, Vigano C, von Schubert C, Nigg E, Schmidt A . Evaluation and Improvement of Quantification Accuracy in Isobaric Mass Tag-Based Protein Quantification Experiments. J Proteome Res. 2016; 15(8):2537-47. DOI: 10.1021/acs.jproteome.6b00066. View

12.

Yoo A, Sun A, Li L, Shcheglovitov A, Portmann T, Li Y . MicroRNA-mediated conversion of human fibroblasts to neurons. Nature. 2011; 476(7359):228-31. PMC: 3348862. DOI: 10.1038/nature10323. View

13.

Li X, Zhao X, Fang Y, Jiang X, Duong T, Fan C . Generation of destabilized green fluorescent protein as a transcription reporter. J Biol Chem. 1998; 273(52):34970-5. DOI: 10.1074/jbc.273.52.34970. View

14.

Townson S, Dobrzycka K, Lee A, Air M, Deng W, Kang K . SAFB2, a new scaffold attachment factor homolog and estrogen receptor corepressor. J Biol Chem. 2003; 278(22):20059-68. DOI: 10.1074/jbc.M212988200. View

15.

Spadotto V, Giambruno R, Massignani E, Mihailovich M, Maniaci M, Patuzzo F . PRMT1-mediated methylation of the microprocessor-associated proteins regulates microRNA biogenesis. Nucleic Acids Res. 2019; 48(1):96-115. PMC: 6943135. DOI: 10.1093/nar/gkz1051. View

16.

Lugert S, Vogt M, Tchorz J, Muller M, Giachino C, Taylor V . Homeostatic neurogenesis in the adult hippocampus does not involve amplification of Ascl1(high) intermediate progenitors. Nat Commun. 2012; 3:670. DOI: 10.1038/ncomms1670. View

17.

Rolando C, Taylor V . Non-canonical post-transcriptional RNA regulation of neural stem cell potential. Brain Plast. 2018; 3(1):111-116. PMC: 5928563. DOI: 10.3233/BPL-170046. View

18.

Giachino C, Basak O, Taylor V . Isolation and manipulation of mammalian neural stem cells in vitro. Methods Mol Biol. 2008; 482:143-58. DOI: 10.1007/978-1-59745-060-7_9. View

19.

Chawla G, Lin C, Han A, Shiue L, Ares Jr M, Black D . Sam68 regulates a set of alternatively spliced exons during neurogenesis. Mol Cell Biol. 2008; 29(1):201-13. PMC: 2612485. DOI: 10.1128/MCB.01349-08. View

20.

Short K, Cox T . Subclassification of the RBCC/TRIM superfamily reveals a novel motif necessary for microtubule binding. J Biol Chem. 2006; 281(13):8970-80. DOI: 10.1074/jbc.M512755200. View