Commissural axon guidance requires complex modulations of growth cone sensitivity to midline-derived cues, but underlying mechanisms in vertebrates remain largely unknown. By using combinations of ex vivo and in vivo approaches, we uncovered a molecular pathway controlling the gain of response to a midline repellent, Semaphorin3B (Sema3B). First, we provide evidence that Semaphorin3B/Plexin-A1 signaling participates in the guidance of commissural projections at the vertebrate ventral midline. Second, we show that, at the precrossing stage, commissural neurons synthesize the Neuropilin-2 and Plexin-A1 Semaphorin3B receptor subunits, but Plexin-A1 expression is prevented by a calpain1-mediated processing, resulting in silencing commissural responsiveness. Third, we report that, during floor plate (FP) in-growth, calpain1 activity is suppressed by local signals, allowing Plexin-A1 accumulation in the growth cone and sensitization to Sema3B. Finally, we show that the FP cue NrCAM mediates the switch of Plexin-A1 processing underlying growth cone sensitization to Sema3B. This reveals pathway-dependent modulation of guidance receptor processing as a novel mechanism for regulating guidance decisions at intermediate targets.[Keywords: Axon guidance; midline crossing; semaphorin; calpain; commissural neurons] Supplemental material is available at http://www.genesdev.org.

Context.-Although tuberculosis (TB) is the leading worldwide cause of death due to an infectious disease, the extent to which progressive clinical disease is associated with genetic host factors remains undefined. Objective.-To determine the distribution of HLA antigens and the frequency of 2 alleles of the tumor necrosis factor ␣ (TNF-␣) gene in unrelated individuals with clinical TB (cases) compared with individuals with no history of clinical TB (controls) in a population with a high prevalence of TB exposure. Design.-A 2-stage, case-control molecular typing study conducted in 1995-1996. Setting.-Three district hospitals in Svay Rieng Province in rural Cambodia. Patients.-A total of 78 patients with clinical TB and 49 controls were included in the first stage and 48 patients with TB and 39 controls from the same area and socioeconomic status were included in the second stage. Main Outcome Measures.-Presence of HLA class I and class II alleles determined by sequence-specific oligonucleotide probe hybridization and presence of 2 TNF-␣ alleles determined by restriction fragment length polymorphism analysis. Results.-In the first stage, 7 DQB1*0503 alleles were detected among 156 alleles derived from patients with TB, whereas no DQB1*0503 alleles were found among the 98 alleles derived from controls (P=.04). There was no detectable difference in the distribution of the 2 TNF-␣ alleles in patients with TB compared with controls. In the second stage, we tested for the presence of a single variable, the DQB1*0503 allele, and found 9 DQB1*0503 alleles among 96 alleles derived from patients with TB and no DQB1*0503 alleles among 78 alleles in controls (P=.005). Conclusions.-The HLA-DQB1*0503 allele is significantly associated with susceptibility to TB in Cambodian patients and, to our knowledge, is the first identified gene associated with development of clinical TB.

The first and last names of the first author, Julien Falk, were transposed. The name is correct as shown in the author list printed here.