Fractures initiate one round of endochondral bone formation in which callus cells differentiate in a synchronous manner that temporally phenocopies the spatial variation of endochondral development of a growth plate. During fracture healing C57BL/6J (B6) mice initiate chondrogenesis earlier and develop more cartilage than bone, whereas C3H/HeJ (C3H) mice initiate osteogenesis earlier and develop more bone than cartilage. Comparison of the transcriptomes of fracture healing in these strains of mice identified the genes that showed differences in timing and quantitative expression and encode for the variations in endochondral bone development of the two mouse strains. The complement of strain-dependent differences in gene expression was specifically associated with ontologies related to both skeletal and vascular formation. Moreover, the differences in gene expression associated with vascular tissue formation during fracture healing were correlated with the underlying differences in development and function of the cardiovascular systems of these two strains of mice. Significant differences in gene expression associated with bone morphogenetic protein/transforming growth factor b (BMP/ TGF-b) signal-transduction pathways were identified between the two strains, and a network of differentially expressed genes specific to the MAP kinase cascade was further defined as a subset of the genes of the BMP/TGF-b pathways. Other signal-transduction pathways that showed significant strain-specific differences in gene expression included the RXR/PPAR and G protein-related pathways. These data identify how bone and vascular regeneration are coordinated through expression of common sets of transcription and morphogenetic factors and suggest that there is heritable linkage between vascular and skeletal tissue development during postnatal regeneration. ß

The p75 kDa neurotrophin receptor (p75NTR) has been detected in a number of non-neural tissues, especially during development. Reports of Trk receptor transcripts in non-neural tissues raise the possibility that the sites of p75NTR expression during development may correlate with Trk receptor expression. Coexpression of p75NTR with the Trk receptors in developing non-neural tissues would support the hypothesis that there is a cooperative function between the two receptor subclasses. To address these questions, p75NTR was localized relative to the three known Trk receptors in adjacent sections of rat embryos at stages of development when the highest levels of p75NTR have been observed in the muscle, maxillary pad, kidney, and lung. Using in situ hybridization and immunhistochemical analyses, we show here that the Trk receptors are expressed extensively in non-neural tissues during cell differentiation and tissue morphogenesis but in patterns that are generally reciprocal to that of p75NTR. The results indicate p75NTR most likely functions independently of the Trk receptors in most developing non-neural tissues. However, the p75NTR consistently appears in non-neural cells adjacent to those expressing Trk receptors. The reciprocal patterns of expression indicate that the separate activities of the two receptors most likely complement each other in regulating cell-cell interactions important for the innervation of developing non-neural tissues.

The p75 kDa neurotrophin receptor (p75NTR) has been detected in a number of non-neural tissues, especially during development. Reports of Trk receptor transcripts in non-neural tissues raise the possibility that the sites of p75NTR expression during development may correlate with Trk receptor expression. Coexpression of p75NTR with the Trk receptors in developing non-neural tissues would support the hypothesis that there is a cooperative function between the two receptor subclasses. To address these questions, p75NTR was localized relative to the three known Trk receptors in adjacent sections of rat embryos at stages of development when the highest levels of p75NTR have been observed in the muscle, maxillary pad, kidney, and lung. Using in situ hybridization and immunhistochemical analyses, we show here that the Trk receptors are expressed extensively in non-neural tissues during cell differentiation and tissue morphogenesis but in patterns that are generally reciprocal to that of p75NTR. The results indicate p75NTR most likely functions independently of the Trk receptors in most developing non-neural tissues. However, the p75NTR consistently appears in non-neural cells adjacent to those expressing Trk receptors. The reciprocal patterns of expression indicate that the separate activities of the two receptors most likely complement each other in regulating cell-cell interactions important for the innervation of developing non-neural tissues.

This study demonstrates that innervation dependent on two different neurotrophin tyrosine kinase (trk) receptors can form the same types of sensory endings (Merkel endings) in the same target (Merkel cells of vibrissa follicles). Some endings transiently express trkA during their initial development, whereas others express trkC throughout their development. Consequently, elimination of kinase domains of either trkA or trkC each result in a partial loss of Merkel endings, whereas absence of kinase domains of both receptors results in a total loss. At the onset of Merkel ending development, at least one kinase-lacking trkC isoform is transiently expressed on all the follicle cells, while neurotrophin 3 is transiently expressed only in the cells at the middle third of the follicle where the Merkel endings and cells develop. This transient non-neuronal expression of truncated trkC is essential for development of any Merkel endings, whereas some Merkel endings and cells still begin to develop in the absence of neurotrophin 3. Therefore, truncated trkC plays a more important role in the development of this innervation than kinase forms of trkA or trkC or of NT3, the only known ligand for trkC receptors.

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