U. Fischer & A. Müller

The role of miR-26b in neurogenesis

Dr. Utz Fischer

University of Wuerzburg
Department of Biochemistry

Am Hubland 97074 Wuerzburg

Phone : +49 9313184029
Fax : +49 8313184028

E-Mail : utz.fischer@biozentrum.uni-wuerzburg.de

Web : See online here

Prof. Dr. Albrecht Mueller

Institut fuer Medizinische Strahlenkunde und Zellforschung

Zinklesweg 10, D-97080 Wuerzburg

Phone : (49) 931 - 201 45848 (Office) - (49) 931 - 201 45478/45146 (Secr.)
Fax : (49) 931 - 201 45148

E-Mail : albrecht.mueller@uni-wuerzburg.de

Web : See online here

A critical step in the differentiation of multipotent neural stem cells (NSCs) into neurons is the coordinated induction of a neuron-specific gene expression program. A major factor within this transcriptional switch is the repressor element silencing transcription factor (REST). REST prevents expression of neuron-specific genes in NSCs and its gradual inactivation leads to a neuron-specific gene expression program that ultimately induces neurogenesis. The repression of neuronal genes is mediated via critical cofactors of REST such as the small phosphatase Ctdsp2. This enzyme dephosphorylates the C-terminal domain of RNA-polymerase II and hence reduces its activity on target genes. Consequently, the spatio-temporal control of Ctdsp2 is a critical step during neuronal differentiation. We have recently shown that the mRNA encoding Ctdsp2 is a target of the micro-RNA miR-26b. miR-26b-mediated repression of ctdsp2 mRNA results in reduced REST activity and the initiation of neurogenesis. Of note, miR-26b is encoded in an intron of the ctdsp2 primary transcript, thus providing the basis of an intrinsic negative feedback loop. We further showed that this feedback loop is inactive in NSCs due to an arrest of miR-processing at the precursor level but it becomes activated in the course of neurogenesis. Based on these studies we wish to uncover the mechanism and factors that regulate miR-26b biogenesis. In the course of our studies we will also analyze at what stage of neuronal differentiation miR-26b acts.

Key Technologies :
- Micromanipulation of Xenopus laevis oocytes
- Micromanipulation and immunohistochemical analysis of Zebrafish
- Functional biochemistry/RNP biochemistry
- Structural biology
- Stem cell biology

Last Publications

- Utz Fischer :
Chari, A., Golas, M., Neuenkirchen, N., Klingenhäger, M., Sander, B., Englbrecht, C., Sickmann, A., Stark, H. and Fischer, U. 2008. An assembly chaperone collaborates with the SMN complex to generate spliceosomal SnRNPs. Cell, 135:497-509.

Günther, UP., Handoko, L., Laggerbauer, B., Chari, A., Sickmann, A., Gehring, N., Sendtner, M., Hübner, C., Schülke, M., von Au, K., and Fischer, U. 2009. IGHMBP2 is a ribosome-associated helicase inactive in the neuromuscular disorder distal SMA type 1. Hum. Mol. Genet. Vol. 18, No. 7 1288–1300.

Linder, B., Dill, H., Hirmer, A., Brocher, J,. Lee, GP., Mathavan, S., Bolz, HJ., Winkler, C., Laggerbauer, B. and Fischer, U. 2011. Systemic splicing factor deficiency causes tissue-specific defects: a zebrafish model for retinitis pigmentosa. Hum. Mol. Genet. 20(2):368-77

Dill, H., Linder ,B., Fehr, A. and Fischer, U. 2012. Intronic miR-26b controls neuronal differentiation by repressing its host transcript, ctdsp2. Genes&Dev. 26(1):25-30.

- Highlighted in a Perspective by Han, Denli and Gage in Genes&Dev. 26(1):6-10

Stoll G, Pietiläinen OP, Linder B, Suvisaari J, Brosi C, Hennah W, Leppä V, Torniainen M, Ripatti S, Ala-Mello S, Plöttner O, Rehnström K, Tuulio-Henriksson A, Varilo T, Tallila J, Kristiansson K, Isohanni M, Kaprio J, Eriksson JG, Raitakari OT, Lehtimäki T, Jarvelin MR, Salomaa V, Hurles M, Stefansson H, Peltonen L, Sullivan PF, Paunio T, Lönnqvist J, Daly MJ, Fischer U*, Freimer NB*, Palotie A. 2013. *Corresponding authors. Deletion of TOP3β, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders. Nat. Neurosci. 16: 1228-1237

- Highlighted in a News and Views article by Nott and Tsai in Nat. Neurosci. 16:1163-1164

- Albrecht Müller :

Schmitt J, Eckardt S, Schlegel PG, Sirén AL, Bruttel VS, McLaughlin KJ, Wischhusen J, Müller AM. Human Parthenogenetic Embryonic Stem Cell-Derived Neural Stem Cells Express HLA-G and Show Unique Resistance to NK Cell-Mediated Killing. Mol Med 2015 Mar 23;21:185-96.

Dinger, TC., Eckardt, S., Choi, SW., Camarero, G., Kurosaka, S., Hornich, V.,
McLaughlin, KJ. and Müller, AM. Androgenetic Embryonic Stem Cells Form Neural Progenitor Cells In Vivo and In Vitro. Stem Cells 2008, 26:1474 -1483.

Obier, N., Uhlemann, CF. and Müller, AM. 2010. Inhibition of histone deacetylases by
Trichostatin A leads to a HoxB4-independent increase of hematopoietic progenitor/stem cell frequencies as a result of selective survival. Cytotherapy 12(7):899-908.

Benedikt et al., The leukemogenic AF4–MLL fusion protein causes P-TEFb kinase
activation and altered epigenetic signatures. Leukemia 2011, 25:135-44

Ahmad, R., Wolber, W., Eckardt, S., Koch, P., Schmitt, J., Semechkin, R., Geis, C.,Heckmann, M., Brüstle, O., McLaughlin, JK., Sirén, AL. and Müller, AM.. Functional neuronal cells generated by human parthenogenetic stem cells. PLoS One 2012, 7(8):e42800.

N Obier, Q Lin, P Cauchy, V Hornich, M Zenke, M Becker and AM Müller, Stem Cell Reviews and Reports, Polycomb protein EED is required for silencing of pluripotency genes upon ESC differentiation. Stem Cell Rev. 2014, PMID: 25134795

Zdzieblo D, Li X, Lin Q, Zenke M, Illich DJ, Becker M, Müller AM. Pcgf6, a Polycomb
Group Protein, Regulates Mesodermal Lineage Differentiation in Murine ESCs and
Functions in iPS Reprogramming. Stem Cells. 2014, 32(12):3112-25

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