Figure 5.

Mechanism of the phenotypic switch in TrkA^TrkC/TrkC mice. (a-d) LacZ-derived activity is apparent in cell bodies (a) and central projections (c) of nociceptive-thermoceptive neurons in mice carrying a single copy of TrkA^τlacZ. This staining is absent in TrkA^τlacZ/TrkC compound heterozygous mice (b,d). (e-h) In situ hybridization analysis shows that DRG neurons from TrkA^TrkC/TrkC;TrkC^-/- double homozygous mice do not express the proprioceptive marker parvalbumin (h), similarly to TrkC^-/- mice (f), indicating that endogenous TrkC is required for the phenotype observed in TrkA^TrkC/TrkC mice (g). (i-k) A model of the mechanism underlying the phenotypic switch described in this study. Neurons in TrkA^TrkC/TrkC mice that initially activate the TrkA promoter now instead express TrkC. This leads to a Trk switch, including the downregulation of the TrkA promoter and upregulation of the endogenous TrkC promoter. (l) Levels of TrkC transgene expression were assessed by semiquantitative RT-PCR at two different time points. GAPDH and peripherin transcripts were used as controls for the cDNA samples. Consistent results were obtained in three different experiments. In agreement with the above model, the transgene was expressed at E13.5 in both TrkA^TrkC and TrkA^TrkC/TrkC mice. Postnatally, the transgene was expressed in heterozygous, but not homozygous, mice. TrkA was absent in all homozygous samples, as expected.