Mart Saarma lab

Contact information

Mart Saarma
Professor
Tel. +358 50 5002726
Fax. +358 2941 59366
e-mail: mart.saarma-at-helsinki dot fi

Institute of Biotechnology
P.O.Box. 56, 00014 University of Helsinki
Street address: Viikinkaari 5D, Biocenter 2

 

 

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Neurotrophic factors outside the nervous system

Work by our group and others have previously shown that neurotrophic factors GDNF family ligands and recently also mesenchephalic astrocyte-derived neurotrophic factor MANF, are vitally important also outside the nervous system. GDNF signaling through the RET receptor tyrosine kinase is essential for induction of kidney morphogenesis (1). GDNF is required for initial ureteric bud outgrowth but the events that occur downstream of RET to promote ureter morphogenesis remain largely obscure. While the molecular control of renal differentiation is relatively well established (2) the downstream events how GDNF/Ret together with its intracellular signaling pathways direct ureteric bud formation and branching morphogenesis at the cellular only start to be elucidated (3, 4). Current specific projects utilize several genetically modified mouse model and focus on understanding 1) the significance of GDNF 3’ UTR for renal differentiation beyond the ureteric bud induction, 2) the function of mitogen activated protein kinase (MAPK) pathway in the control of ureteric bud branching and 3) the  in vivo relevance of Ret-independent GDNF signaling in renal differentiation. Additionally, in vitro kidney cultures are used as an assay to test biological function/activity (5) of different neurotrophic factors aiming to be used in therapy of neurological diseases.

Furthermore, our group recently demonstrated that MANF is indispensable for the development of the proper insulin-producing beta cell mass in the pancreas of mice (6). Importantly, MANF protein enhanced b-cell proliferation in vitro and overexpression of MANF in the pancreasof diabetic mice enhanced b-cell regeneration, indicating that MANF might have therapeutic potential for the treatment of diabetes. With Prof. Hannu Sariola´s group, we have shown that GDNF is an important regulator of spermatogenesis (7). We have discovered and characterized the mammalian receptor for persephin, GFRα4, which in contrast to other GFRα- receptors is mainly expressed in endocrine cells (8) and is together with RET upregulated in medullary thyroid tumors (9). Gene-knockout studies revealed that Gfrα4/Ret signalling in the thyroid gland regulates calcitonin synthesis and thereby calcium homeostasis, which may be relevant in human osteoporosis (10).  Furthermore, soluble GFRα4 can in the absence of PSPN ligand, directly activate RET (11). We have also found that oncogenic RET MEN2B can signal already in the ER on his way to the plasma membrane (12).

 

1. Pichel, J.G., L. Shen, H.Z. Sheng, A.C. Granholm, J. Drago, A. Grinberg, E.J. Lee, S.P. Huang, M. Saarma, B.J. Hoffer, H. Sariola, and H. Westphal, Defects in enteric innervation and kidney development in mice lacking GDNF. Nature. 382(6586): 73-6 (1996).

2. Kuure S, Vuolteenaho R, Vainio S. Kidney morphogenesis: cellular and molecular regulation. Mech Dev. 92(1): 31-45 (2000).

3. Kuure, S., Cebrian, C., Machingo, Q., Lu, B.C., Chi, X., Hyink, D., D'Agati, V., Gurniak, C., Witke, W. and F. Costantini . Actin depolymerizing factors cofilin1 and destrin are required for ureteric bud branching morphogenesis. PLoS Genet. 6:e1001176 (2010).

4. Kuure, S., Chi,. X., Lu, B., Costantini, F. The transcription factors Etv4 and Etv5 mediate formation of the ureteric bud tip domain during kidney development. Development. 137:1975-1979 (2010).

5. Sainio, K., P. Suvanto, J. Davies, J. Wartiovaara, K. Wartiovaara, M. Saarma, U. Arumae, X. Meng, M. Lindahl, V. Pachnis, and H. Sariola, Glial-cell-line-derived neurotrophic factor is required for bud initiation from ureteric epithelium. Development. 124(20): 4077-87 (1997).

6. Lindahl, M., Danilova, T., Palm, E., Lindholm, P., Võikar, V., Hakonen, E., Ustinov, J., Andressoo, J-O., Harvey, B.K., Otonkoski, T., Rossi, J. and Saarma, M. MANF is indispensable for the proliferation and survival of pancreatic b-cells. Cell Reports, in press (2014).

7. Meng, X., Lindahl, M., Hyvönen, M.E,. Parvinen, M., de Rooij, D.G., Hess, M.W., Raatikainen-Ahokas, A., Sainio, K., Rauvala, H., Lakso, M., Pichel, J.G., Westphal, H., Saarma, M. and Sariola, H. Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science, 287, 1489-1493 (2000).

8. Lindahl, M., Timmusk, T., Rossi, J., Saarma, M and Airaksinen, M.S. Expression and alternative splicing of mouse Gfra4 suggests roles in endocrine cell development. Mol. Cell. Neurosci. 15, 522-533 (2000).

9. Lindahl, M., Poteryaev, D., Liying, Y., Arumäe, U., Timmusk, T., Bongarzone, I., Aiello, A., Pierotti, M. A., Airaksinen, M. A. & Saarma, M. Human glial cell line-derived neurotrophic factor receptor a4 is the receptor for persephin and is predominantly expressed in normal and malignant thyroid medullary cells. J. Biol. Chem. 276, 9344-9351 (2001).

10. Lindfors P.H., Lindahl M., Rossi J., Saarma M., Airaksinen M.S. Ablation of persephin receptor glial cell line-derived neurotrophic factor family receptor alpha4 impairs thyroid calcitonin production in young mice.
Endocrinology. 147(5):2237-44 (2006)

11. Yang, J., Lindahl, M., Lindholm, P., Virtanen, H., Coffey, E., Runeberg-Roos, P., Saarma, M. PSPN/GFRalpha4 has a significantly weaker capacity than GDNF/GFRalpha1 to recruit RET to rafts, but promotes neuronal survival and neurite outgrowth. FEBS Letters 569, 267-71 (2004)

12. Runeberg-Roos P, Virtanen H, Saarma M. RET(MEN 2B) is active in the endoplasmic reticulum before reaching the cell surface. Oncogene 26:7909-15 (2007)