The Expression of Receptor Tyrosine Phosphatases Is Responsive to Sciatic Nerve Crush Kim Haworth,* Kai Keen Shu, ² Alex Stokes, ² Roger Morris, ² and Andrew Stoker* ,1 *Department of Human Anatomy, University of Oxford, Oxford OX1 3QX; and † Department of Experimental Pathology, UMDS, Guy’s Hospital, London, United Kingdom Given the importance of phosphotyrosine signaling in growth cone dynamics, we have examined the embryonic and adult expression of receptor-like protein tyrosine phosphatases in sensory neurons and studied their re- sponsiveness to nerve lesions in young adult animals. The phosphatases LAR, PTP, and PTP are expressed in most neurons of E14 and E18 rat embryo dorsal root ganglia, while BEM-1 is expressed in a more restricted subset of these neurons. These phosphatases continue to be expressed in young adult animals, suggesting that they have roles in mature as well as in developing dorsal root ganglia neurons. After an experimental sciatic nerve crush, the expression of the phosphatase genes was signifi- cantly and differentially altered in these neurons. PTP mRNA was increased by 50% after 3 days, while LAR and PTP expression dropped by 50 and 20%, respectively. BEM-1 mRNA levels were unaltered. These data show that mRNA levels of specific tyrosine phosphatase genes are highly responsive to nerve damage and may be reset to a new and potentially optimal pattern of expression more conducive for nerve regeneration. We propose that tyro- sine phosphatases are not only involved in primary axono- genesis but can also now be implicated in the molecular control of adult nerve repair. INTRODUCTION Although the molecular mechanisms underlying axo- nal growth and repair are still poorly understood, many of the potential signaling components in the growth cone membrane are now characterized. Cell adhesion molecules (CAMs) and receptors for substrate adhesion molecules have been characterized in nerve cell mem- branes, and the manners in which these regulate growth cone adhesion and movement are being unraveled (Tessier-Lavigne and Goodman, 1996). In particular, the key role of protein tyrosine kinases (PTKs) in axon growth and guidance has become increasingly appar- ent. This is exemplified by the actions of ephrin receptor PTKs (Drescher et al., 1995; Henkemeyer et al., 1996; Orike and Pini, 1996) as well as the functional interac- tions seen between the FGF receptor PTK and a number of neuronal CAMs (Williams et al., 1994). The emergence of phosphotyrosine signaling as a component of axonal regulation has necessarily focused attention on the role of protein tyrosine phosphatases (PTPases). More than 75 of these enzymes have so far been identified and many are expressed in the nervous system (Brady-Kalney and Tonks, 1995; Stoker and Dutta, 1998). Significantly, neural PTPases are fre- quently transmembrane in structure and many are members of the immunoglobulin superfamily. Of these, several also exist in alternative protein isoforms, some of which are neural specific (Mizuno et al., 1993; Stoker, 1994; Zhang and Longo, 1995; Zhang et al., 1998). It is therefore predicted that growth cones will use the adhesive and signaling potentials of receptor phosphata- ses for the direct control of axonogenesis. Consistent with this idea, R-PTPases in vertebrates and in flies have been localized in axons and their growth cones (Stoker et al., 1995; Krueger et al., 1996). Direct evidence of their axonal function comes from Drosophila, in which muta- tions in three neural R-PTPases, DLAR, DPTP99A, and DPTP64D, reveal a set of defects in motor nerve guid- ance affecting axon fasciculation and the recognition of target cells (Desai et al., 1996, 1997; Krueger et al., 1996). After nerve damage in an adult animal, axon re- growth is essential for the reestablishment of target 1 Present address: Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH. MCN Molecular and Cellular Neuroscience 12, 93–104 (1998) Article No. CN980707 93 1044-7431/98 $25.00 Copyright  1998 by Academic Press All rights of reproduction in any form reserved.