Urokinase and urokinase receptor participate in regulation of neuronal migration, axon growth and branching.
OBJECTIVE
Recent findings indicate the significant contribution of urokinase and urokinase receptor (uPA and uPAR) in the processes of nerve regeneration, however, their role in axonal growth and branching is unclear. Using a 3D model of mouse Dorsal Root Ganglia (DRG) explants, differentiated into neurons Neuro 2a cells and transgenic mice lacking the urokinase gene, we studied the involvement of the uPA/uPAR system in the neural cell migration, neurite outgrowth, elongation and branching.


RESULTS
uPA and uPAR are expressed in the growth cones of axons. Using an ex vivo model of DRG explants in Matrigel we have found that uPA inhibition attenuates neural cell migration and axonal growth, pointing to an important role of urokinase in these processes. Apparently, uPA mediates its effects through its specific receptor uPAR: anti-uPAR antibody, which blocks the uPA binding to uPAR, stimulates axon branching and attenuates neural cell migration from DRG explants. Simultaneous inhibition of uPA and uPAR almost completely prevents the axonal outgrowth from explants into the Matrigels. Experiments in vitro using Neuro 2a cells differentiated into neurons demonstrate that administration of exogenous uPA increases the neurite growth rate (elongation), most likely via the interaction of uPA with uPAR. Blocking of uPAR stimulates neurite formation and enhances branching of preexisting neurites. The results obtained on DRG explants from transgenic mice lacking uPA gene support the assumption that uPA stimulates neurite growth via uPA/uPAR interaction and uPAR role in axons branching and neural cell migration.


CONCLUSIONS
The uPA/uPAR system plays an essential role in neural cell migration, axonal growth and branching.
Department of Biochemistry and Molecular Medicine, Faculty of Medicine, M.V. Lomonosov Moscow State University, Lomonosovsky av. 31/5, 119192 Moscow, Russian Federation; Laboratory of Molecular Endocrinology, Russian Cardiology Research Center, 3rd Cherepkovskaya 15a, 12155 Moscow, Russian Federation.
Ekaterina
E
Semina
Department of Biochemistry and Molecular Medicine, Faculty of Medicine, M.V. Lomonosov Moscow State University, Lomonosovsky av. 31/5, 119192 Moscow, Russian Federation. Electronic address: rkseniya@mail.ru.
Kseniya
K
Rubina
Department of Biochemistry and Molecular Medicine, Faculty of Medicine, M.V. Lomonosov Moscow State University, Lomonosovsky av. 31/5, 119192 Moscow, Russian Federation.
Veronika
V
Sysoeva
Department of Biochemistry and Molecular Medicine, Faculty of Medicine, M.V. Lomonosov Moscow State University, Lomonosovsky av. 31/5, 119192 Moscow, Russian Federation.
Karina
K
Rysenkova
Department of Biochemistry and Molecular Medicine, Faculty of Medicine, M.V. Lomonosov Moscow State University, Lomonosovsky av. 31/5, 119192 Moscow, Russian Federation.
Polina
P
Klimovich
Laboratory of Molecular Endocrinology, Russian Cardiology Research Center, 3rd Cherepkovskaya 15a, 12155 Moscow, Russian Federation.
Olga
O
Plekhanova
Department of Biochemistry and Molecular Medicine, Faculty of Medicine, M.V. Lomonosov Moscow State University, Lomonosovsky av. 31/5, 119192 Moscow, Russian Federation; Laboratory of Molecular Endocrinology, Russian Cardiology Research Center, 3rd Cherepkovskaya 15a, 12155 Moscow, Russian Federation.
Vsevolod
V
Tkachuk
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009416:Nerve Regeneration; D000071446:Neuronal Outgrowth / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D009924:Organ Culture Techniques; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator
3D explants of Dorsal Root Ganglia (DRG); Axon branching; Axon growth; Neuronal migration; Urokinase; Urokinase receptor