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The Journal of Neuroscience, May 31, 2006, 26(22):5872-5880; doi:10.1523/JNEUROSCI.0386-06.2006

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Development/Plasticity/Repair
Mammalian Motoneuron Axon Targeting Requires Receptor Protein Tyrosine Phosphatases and

Noriko Uetani,¹ Mélanie J. Chagnon,¹ Timothy E. Kennedy,² Yoichiro Iwakura,³ and Michel L. Tremblay¹

¹McGill Cancer Centre and Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 1Y6, ²Centre for Neuronal Survival, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4, and ³Center for Experimental Medicine, Institute of Medical Sciences, University of Tokyo, Tokyo 108-8639, Japan

Correspondence should be addressed to Michel L. Tremblay, McGill Cancer Centre, McIntyre Medical Sciences Building, McGill University, 3655 Promenade Sir-William-Osler, Room 701, Montreal, Quebec, Canada H3G 1Y6. Email: michel.tremblay{at}mcgill.ca

The leukocyte common antigen-related (LAR) subfamily of receptor protein tyrosine phosphatases (RPTPs), LAR, RPTP-, and RPTP-, regulate neuroendocrine development, axonal regeneration, and hippocampal long-term potentiation in mammals. In Drosophila, RPTPs are required for appropriate axon targeting during embryonic development. In contrast, deletion of any one of the three LAR-RPTP family members in mammals does not result in gross axon targeting defects. Both RPTP- and RPTP- are highly expressed in the developing mammalian nervous system, suggesting they might be functionally redundant. To test this hypothesis, we generated RPTP- and RPTP- (RPTP-/) double-mutant mice. Although embryonic day 18.5 RPTP- and RPTP- single-mutant embryos were viable, RPTP-/ double mutants were paralyzed, were never observed to draw a breath, and died shortly after cesarean section. RPTP-/ double mutants exhibit severe muscle dysgenesis and severe loss of motoneurons in the spinal cord. Detailed analysis of the projections of phrenic nerves in RPTP-/ double mutants indicated that these motoneuron axons emerge normally from the cervical spinal cord, but stall on reaching the diaphragm. Our results demonstrate that RPTP- and RPTP- complement each other functionally during mammalian development, and reveal an essential contribution of RPTP- and RPTP- to appropriate motoneuron axon targeting during mammalian axonogenesis.

Key words: protein tyrosine phosphatase; tyrosine phosphorylation; axon targeting; axon guidance; motoneuron (motor neuron); phrenic; ;

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Received June 27, 2005; revised April 18, 2006; accepted April 19, 2006.

Correspondence should be addressed to Michel L. Tremblay, McGill Cancer Centre, McIntyre Medical Sciences Building, McGill University, 3655 Promenade Sir-William-Osler, Room 701, Montreal, Quebec, Canada H3G 1Y6. Email: michel.tremblay{at}mcgill.ca

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