Motor function depends on the formation of selective connections between sensory and motor neurons and their muscle targets. The molecular basis of the specificity inherent in this sensory-motor circuit remains unclear. We show that motor neuron pools and subsets of muscle sensory afferents can be defined by the expression of ETS genes, notably PEA3 and ER81. There is a matching in PEA3 and ER81 expression by functionally interconnected sensory and motor neurons. ETS gene expression by motor and sensory neurons fails to occur after limb ablation, suggesting that their expression is coordinated by signals from the periphery. ETS genes may therefore participate in the development of selective sensory-motor circuits in the spinal cord.

1. The development of motoneurone projection patterns in the chick hind limb from reversed spinal cord segments was studied from the onset of axonal outgrowth (St. 24) to the establishment of mature connectivity patterns (St. 36). Approximately the first three lumbosacral cord segments were reversed along the anterior-posterior axis at St. 15-16. 2. Projection patterns from reversed cord segments were assessed electrophysiologically by direct spinal cord and spinal nerve stimulation and anatomically by retrograde horseradish peroxidase (HRP) labelling of motoneurones in St. 30-36 embryos. In younger embryos, paths taken by reversed axons were characterized by orthograde HRP labelling of motoneurones in specific reversed cord segments. 3. Lumbosacral motoneurones formed appropriate functional connexions with individual limb muscles in spite of anterior-posterior shifts in their spinal cord position aned consequent shifts in their spinal nerve entry point into the limb bud. Reversed motoneurones supplying individual hind limb muscles formed discrete nuclei in the transverse plane of the cord. Each nucleus and the lateral motor column as a whole showed reversed topographical characteristics when compared to control embryos. These observations were made before (St. 30) and after (St. 35-36) the major period of motoneurone cell death. 4. Correct connectivity resulted from specific alterations in axonal pathways within the plexus or major nerve trunks proximal to the branching of individual muscle nerves. Further such directed outgrowth was present from the earliest times that axons could be traced into the limb which is before the onset of motoneurone cell death and muscle cleavage. 5. It is concluded that motoneurones are specified to project to individual muscles or to follow particular pathways prior to motoneurone birthdays and limb bud formation. The establishment of specific motoneurone connectivity can not be accounted for by passive or mechanical guidance models alone. Rather, motoneurones must also actively respond to cues within the limb or interact among themselves on the basis of an early central specification.

An increasing number of medical schools have implemented or are considering implementing scholarly activity programs as part of their undergraduate medical curricula. The goal of these programs is to foster students' analytical skills, enhance their self-directed learning and their oral and written communication skills, and ultimately to train better physicians. In this article, the authors describe the approach to implementing scholarly activities at a school that requires this activity and at a school where it is elective. Both programs have dealt with significant challenges including orienting students to a complex activity that is fundamentally different than traditional medical school courses and clerkships, helping both students and their mentors understand how to "stay on track" and complete work, especially during the third and fourth years, and educating students and mentors about the responsible conduct of research, especially involving human participants. Both schools have found the implementation process to be evolutionary, requiring experience before faculty could significantly improve processes. A required scholarly activity has highlighted the need for information technology (IT) support, including Web-based document storage and student updates, as well as automatic e-mails alerting supervisory individuals to student activity. Directors of the elective program have found difficulty with both ensuring uniform outcomes across different areas of study and leadership changes in a process that has been largely student-driven. Both programs have found that teamwork, regular meetings, and close communication have helped with implementation. Schools considering the establishment of a scholarly activity should consider these factors when designing programs.

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Members of the Spalt gene family encode putative transcription factors characterized by seven to nine C2H2 zinc finger motifs. Four genes have been identified in mice-Spalt1 to Spalt4 (Sall1 to Sall4). Spalt homologues are widely expressed in neural and mesodermal tissues during early embryogenesis. Sall3 is normally expressed in mice from embryonic day 7 (E7) in the neural ectoderm and primitive streak and subsequently in the brain, peripheral nerves, spinal cord, limb buds, palate, heart, and otic vesicles. We have generated a targeted disruption of Sall3 in mice. Homozygous mutant animals die on the first postnatal day and fail to feed. Examination of the oral structures of these animals revealed that abnormalities were present in the palate and epiglottis from E16.5. In E10.5 embryos, deficiencies in cranial nerves that normally innervate oral structures, particularly the glossopharyngeal nerve (IX), were observed. These studies indicate that Sall3 is required for the development of nerves that are derived from the hindbrain and for the formation of adjacent branchial arch derivatives.

Hox genes encode anterior-posterior identity during central nervous system development. Few studies have examined Hox gene function at lumbosacral (LS) levels of the spinal cord, where there is extensive information on normal development. Hoxd10 is expressed at high levels in the embryonic LS cord but not the thoracic cord. To test the hypothesis that restricted expression of Hoxd10 contributes to the attainment of an LS identity, and specifically an LS motoneuron identity, Hoxd10 was ectopically expressed in thoracic segments in chick embryos by means of in ovo electroporation. Regional motoneuron identity was assessed after the normal period of motoneuron differentiation. Subsets of motoneurons in transfected thoracic segments developed a molecular profile normally shown by LS motoneurons, including Lim 1 and RALDH2 expression. In addition, motoneurons in posterior thoracic segments showed novel axon projections to two muscles in the anterodorsal limb, the sartorius and anterior iliotibialis muscles. At thoracic levels, we also found a decrease in motoneuron numbers and a reduction in gonad size. These last findings suggest that early and high levels of Hox expression impeded motoneuron development and neural-mesodermal interactions. Despite these adverse effects, our data indicate that Hoxd10 expression is sufficient to induce LS motoneuron identity and axon trajectories characteristic of motoneurons in the LS region.

In the chick, sensory neurons grow to their segmentally appropriate target sites in the hindlimb from the outset during normal development. To elucidate the underlying mechanisms, we performed various manipulations of the neural tube, including the neural crest, or of the hindlimb, before axonal outgrowth and assessed the resulting sensory projections using retrograde and anterograde HRP labeling and electrophysiological techniques. Previous experiments had shown that motoneurons are specified to project to their appropriate target muscles prior to axon outgrowth and that they respond to cues in the limb in order to grow to those targets (C. Lance-Jones and L. Landmesser, 1980, J. Physiol. (London) 302, 559-602; C. Lance-Jones and L. Landmesser, 1981, Proc. R. Soc. London, B 214, 19-52). When several segments of neural tube and neural crest were deleted, sensory neurons in the remaining segments still projected along their correct pathways, as did motoneurons. In situations in which motoneurons grew to their correct targets from altered positions with respect to the limb (e.g., small neural tube reversals), sensory neurons also tended to project along the segmentally appropriate pathways both to skin and to muscle. In situations in which motoneurons were displaced greater distances from their normal point of entry into the limb and made wrong connections (e.g., large neural tube reversals, anterior-posterior limb reversals), sensory neurons also projected incorrectly. The patterns of sensory projections to muscles were, in each situation, generally similar to the motoneuron projections. These results are consistent with the possibility that sensory neurons, like motoneurons, are specified with respect to their peripheral connectivity. Alternatively, the results suggest that motoneurons may play a role in the process of pathway selection by sensory neurons.

To characterize cues used by motoneuron axons to reach their appropriate targets, connectivity patterns within the embryonic chick hindlimb have been analysed after early experimental manipulations of the limb or spinal cord. The manipulations altered the anterior–posterior (a.–p.) relationship between motoneurons within the lumbosacral motor column and their specific targets in the limb. Primary emphasis was placed on analysing the pathways taken by embryonic motoneuron axons at stages 23–36 which had been orthogradely labelled by horseradish peroxidase (HRP) injection into the motor column. Motoneuron pool topography and functional patterns of connectivity were also identified by retrograde HRP labelling and spinal cord stimulation coupled with electromyogra­phic recording. With small shifts in position, as in two or three segment a.–p. cord reversals or a.–p. limb shifts, motoneuron axons frequently entered the appropriate plexus but in an inappropriate spinal nerve sequence. Despite this, axons altered their course to innervate specifically and consistently their correct target. When motoneuron axons entered an inappropriate plexus as the result of a greater positional shift (i. e. more extensive cord reversal or limb shift) or in experiments where posterior cord segments were replaced with anterior cord segments and supernum­erary limbs were added, they behaved in one of two ways.They either formed inappropriate and largely unpatterned or unordered connections or they took totally aberrant paths within the limb to reach their appropriate target. We conclude that axons are capable of responding in a precise and specific manner to environmental cues when displaced up to a certain distance from their target or normal point of entry into the limb. Their failure to form patterned connections at more extreme distances suggests that the cues to which they are responding may be local, or that an axon’s ability to respond to them is restricted to subclasses of the motoneuron population.