Neurotrophins and their Trk family receptor tyrosine kinases act on the development and function of the PNS. Numerous in vitro and in vivo studies have established the roles of each Trk receptor in neurite outgrowth, survival and differentiation

Neurotrophins and their Trk family receptor tyrosine kinases act on the development and function of the PNS. Numerous in vitro and in vivo studies have established the roles of each Trk receptor in neurite outgrowth, survival and differentiation (Bibel and Barde, 2000; Huang and Reichardt, 2001; Snider, 1994). The differential expression of Trk receptors in subsets of sensory neurons indicates that Trk receptor expression and sensory neuron differentiation are closely related processes. For example, regulation of the expression of Trk family receptor is fundamental to the appropriate appearance and survival of sensory neurons. TrkA (Ntrk1 – Mouse Genome Informatics), the prototype of the Trk gene family and the receptor for nerve growth factor (NGF), is required for the survival of nociceptive sensory and sympathetic neurons (Martin-Zanca et al., 1990; Smeyne et al., 1994). In the murine PNS, TrkA expression is confined to neural-crest-derived sensory neurons, including trigeminal and dorsal root ganglia, from early embryonic stages (E9.5) to adults. TrkA is also expressed in sympathetic neurons from E16.5 onwards (Martin-Zanca et al., 1990; Tessarollo et al., 1993). In the CNS, TrkA expression is described in only a subset of cholinergic neurons in the basal forebrain (Holtzman et al., 1992). Understanding the molecular mechanisms for TrkA expression is important to dissect the biological processes regulating the survival and differentiation of sensory and sympathetic neurons. One approach to identify transcriptional regulators of TrkA is to search for known transcription factors that are expressed in sensory neurons during mouse embryonic development and whose loss-of-function lead to alterations of TrkA expression. The POU-homeodomain transcription factor Brn3a (Pou4f1 – Mouse Genome Informatics) (Gerrero et al., 1993; He et al., 1989; Ninkina et al., 1993; Xiang et al., 1993) stands out as an attractive candidate. Brn3a is expressed early in emerging sensory neurons (Artinger et al., 1998; Fedtsova and Turner, 1995) and mutation of this gene in mice leads to abnormal development and loss of neurons that express TrkA, TrkB (Ntrk2 – Mouse Genome Informatics) and TrkC (Ntrk3 – Mouse Genome Informatics) (Eng et al., 2001; Huang et al., 2001; Huang et al., 1999; McEvilly et al., 1996; Xiang et al., 1996). However, questions remain about why and how TrkA becomes downregulated in Brn3a-null sensory neurons. Whether Brn3a is a requisite transcriptional regulator of the TrkA enhancer or an indirect mediator of TrkA expression is unresolved. Previously, we identified a TrkA minimal enhancer that confers specific expression of β-galactosidase transgenes in PNS sensory neurons (Ma et al., 2000). Through mutational analysis in transgenic mice, multiple important, cis-elements were identified. These results indicate that the tightly regulated 3525 Development 130, 3525-3534 © 2003 The Company of Biologists Ltd doi:10.1242/dev.00582