Ludwig Institute for Cancer Research Ltd, Stockholm Branch

Research Groups

Stem Cell Biology Group

Jonas Muhr
Ludwig Institute for Cancer Research Ltd
Karolinska Institutet
Box 240
SE-171 77 Stockholm
Sweden

Visiting Address: Nobels Väg 3

Phone: +46 8 524 871 57
Fax: +46 8 33 28 12

J. Muhr  Ph.D., Associate Member

The central nervous system in human is estimated to contain more than 10¹¹ neurons belonging thousands of different sub-types. To understand how this immense array of neural cell types can be generated an important goal of our research is to examine how the developmental competence of neural stem cells is regulated in time and space. In addition, we are examining molecular similarities and differences between somatic stem cells and cells contributing to the development of brain tumors.

We have demonstrated that transcription factors of the Sox family have significant regulatory roles from early to late stages of neural development (Bylund et al., 2003; Sandberg et al., 2005; Bergsland et al., 2006; 2011). An important aim of our research is to understand how different classes of Sox proteins, acting at different stages of neural lineage development, collaborate to regulate the temporal and spatial expression of large sets of neural genes (Fig. 1). To address these questions the laboratory uses a wide range of technologies including gain- and loss-of-function studies in mouse and chick as well as many current methods in molecular biology, including ChIP-seq, mRNA-seq and profiling of DNA and histone modifications.

Fig. 1. Sequentially acting Sox transcription factors in neural lineage formation. Apart from binding and activating many genes in ES cells, Sox2 pre-binds also many silent genes that later are activated by Sox3 in NPCs. similarly, Sox3 pre-binds thousands of silent genes that later are bound and activated by Sox11 in differentiating neurons

A second focus of our research is to understand how neural stem cells of the adult brain are prevented from contributing to glioma development. To address this issue we are using mouse genetics to examine the tumor suppressor function of a class of Sox proteins expressed in adult neural stem cells (Fig. 2). With these techniques we can functionally test the potential of neural stem cell expressed Sox proteins in preventing brain tumor development and growth.

Fig.2 Tumor suppressor function of Sox proteins. Conditional ablation of Sox proteins in stem cells of the SVZ greatly enhances the glioma inducing capacity of virally expressed onco-genes. Image of an H&E-stained section in which darker area indicates increased cellular density of the tumor.

The Group

Combeau, Gaelle  Postdoctoral Fellow Hagey, Daniel  Ph.D. Student Karlén, Alexandra  Postdoctoral Fellow Klum, Susanne  Ph.D. Student Kurtsdotter, Idha  Ph.D. Student Rezaian, Soheilla  Senior Technician Topcic, Danijal  Postdoctoral Fellow Zaouter, Cécile  Ph.D. Student Gaelle

Selected Publications

• Bergsland, M., Ramsköld, D., Zaouter, C., Klum, S., Sandberg, R., Muhr J. (2011). Neural lineage specification is maintained through sequentially acting Sox transcription factors. Genes & Development 25, 2453-2464.
• Holmberg J., He X., Peredo I., Orrego A., Hesselager G., Ericsson C., Oba-Shinjo S., Nagahashi S., Nistér M., Muhr J. (2011). Activation of Neural and Pluripotent Stem Cell Signatures Correlates with Increased Malignancy in Human Glioma. PloS One 6, e18454.
• Marklund U., Hansson E.M., Sundström E., Hrabé de Angelis M, Przemeck G.K.H, Lendahl U., Muhr J.*, and Ericson J .* (2010). Domain-specific control of neurogenesis achieved through patterned regulation of Notch ligand expression. Development 137, 437-445.
• Holmberg, J., Hansson, E., Malewicz, M., Sandberg, M., Perlmann, T., Lendahl, U., and Muhr, J. (2008). SoxB1 transcription factors and Notch signaling use distinct mechanisms to regulate proneural gene function and neural progenitor differentiation. Development 135, 1843-1851.
• Bergsland M., Werme M., Malewicz M., Perlmann T. and Muhr J. (2006) The establishment of neuronal properties is controlled by Sox4 and Sox11. Genes Dev. 20:3475-3486.
• Sandberg M., Källström M. and Muhr J. (2005) Sox21 promotes the progression of vertebrate neurogenesis. Nat. Neurosci. 8, 995-1001.
• Bylund M., Andersson E., Novitch B.G. and Muhr J. (2003) Vertebrate neurogenesis is counteracted by Sox1-3 activity. Nat. Neurosci. 6, 1162-1168.

Theses

• Regulation of Neurogenesis In the Vertebrate CNS. Magdalena Källström 14-Mar-2008
• Sox Proteins and Neurogenesis Magnus Sandberg 23-Apr-2010
• From Stem Cell to Neuron – a Sox Perspective Maria Bergsland 21-May-2010