Diverse gene expression and function of semaphorins in developing lung: positive and negative regulatory roles of semaphorins in lung branching morphogenesis

Background: Previously, we reported that Sema3A, one of the secreted repuls ive axon guidance molecules, CRMP (collaprin response mediator protein)-2, a putative intracellular signalling molecule for Sema3A and Sema3A receptor neuropilin-1 are expressed in the developing lung. Sema3A inhibits branchi ng morphogenesis of embryonic lung in organ culture. Results: We examined the gene expression of Sema3A, Sema3C, Sema3F and thei r receptors, NP-1, NP-2 and plexin-A1 by in situ hybridization. Transcripts of all six genes were detected in mouse lung from embryonic day E11.5 to E 17.5, acid displayed highly specific spatiotemporal distributions, The dist ribution of the receptor genes was detected in patterns which were consiste nt with known receptor usage of the semaphorins, In contrast to Sema3A, we found that the other class 3 semaphorins, Sema3C and Sema3F, stimulated bra nching morphogenesis. This stimulatory effect of Sema3C or Sema3F was accom panied by a moderate increase in the incorporation of bromodeoxyuridine (Br dU) into DNA in the terminal epithelial cells. Conclusion: The coordinated expression patterns of different semaphorins an d their receptors, together with the specific activities affecting branchin g morphogenesis, suggest that the semaphorins act as both positive and nega tive regulators of branching morphogenesis in the developing lung.