The Paired Homeodomain Protein DRG11 Is Required for the Projection of Cutaneous Sensory Afferent Fibers to the Dorsal Spinal Cord (original) (raw)

216-76 and Howard Hughes Medical Institute The accurate perception of external sensory information California Institute of Technology by the brain requires appropriate synaptic connectivity Pasadena, California 91125 between peripheral sensory neurons of a given modality, 2 Departments of Anatomy and their central targets. How such central connectivity and Physiology and is coordinated with the specification of sensory modality W.M. Keck Foundation Center is poorly understood, and remains a central problem in for Integrative Neuroscience neural development. In the mammalian olfactory sys-University of California, San Francisco tem, for example, a family of odorant receptors (Buck San Francisco, California 94143 and Axel, 1991) both determines sensory modality and 3 Instituto de Histologia e Embriologia contributes to the specificity of topographic projections Universidade do Porto to the olfactory bulb (Wang et al., 1998). Whether such Porto a conservative mechanism for coordinating sensory Portugal modality and connectivity is employed by other devel-4 Department of Neurology and oping sensory systems is not clear, however. PVA/EPVA Neuroscience Research Center Primary somatosensory neurons in mammalian dorsal Yale Medical School root ganglia (DRG) are a heterogeneous population sub-New Haven, Connecticut 06510 serving diverse sensory modalities, including pain, and Rehabilitation Research Center touch, and body position (Scott, 1992). These different VA Medical Center modalities are associated with topographically distinct West Haven, Connecticut 06516 projections to the spinal cord, the first relay station in 5 Department of Anesthesia and Critical Care the central nervous system (CNS). For example, large Massachusetts General Hospital diameter muscle stretch receptor neurons project to the Harvard Medical School ventral spinal cord (Figure 1A, red), while cutaneous Boston, Massachusetts 02129 afferent neurons project to superficial laminae I and II of the dorsal horn (Willis and Coggeshall, 1991) (Figure 1A, blue and green). The latter population includes neurons specialized for nociception, the sensation of nox-Summary ious stimuli. Low-threshold mechanosensory neurons, in turn, project to deeper layers III and IV (Brown et al., Cutaneous sensory neurons that detect noxious stim-1977; Ralston et al., 1984; Shortland et al., 1989). Thus, uli project to the dorsal horn of the spinal cord, while to a first approximation different stimulus features of those innervating muscle stretch receptors project to primary sensory neurons are topographically mapped the ventral horn. DRG11, a paired homeodomain tranto different laminae of the spinal cord (Figure 1A). scription factor, is expressed in both the developing The molecular mechanisms that govern the connectivdorsal horn and in sensory neurons, but not in the ity of different subsets of primary sensory neurons with ventral spinal cord. Mouse embryos deficient in DRG11 their central targets are only beginning to be understood. display abnormalities in the spatio-temporal pat-Semaphorins and their receptors, the neuropilins (He terning of cutaneous sensory afferent fiber projections and Tessier-Lavigne, 1997; Kolodkin et al., 1997), have to the dorsal, but not the ventral spinal cord, as well been proposed to control the projections of cutaneous as defects in dorsal horn morphogenesis. These early versus muscle sensory afferent fibers into the dorsal developmental abnormalities lead, in adults, to signifiversus ventral spinal cord based on in vitro assays (Mescantly attenuated sensitivity to noxious stimuli. In consersmith et al., 1995; Puschel et al., 1996). However, trast, locomotion and sensori-motor functions appear these molecules have not yet been shown to be essential normal. Drg11 is thus required for the formation of for this process in vivo (Kitsukawa et al., 1997; Chen et spatio-temporally appropriate projections from nocial., 2000; Giger et al., 2000). Similarly, in vitro studies have suggested that Slit molecules may control the initial branching of sensory afferent fibers into the spinal