It is well established that the neurotransmitter serotonin performs essential functions during the course of vertebrate development. The objective of this study was to examine the role of serotonin in the development of two species of frogs that have evolved different developmental modes: direct development and metamorphosis. Directly developing frogs lack the free-swimming, larval stage that is characteristic of most metamorphic frogs and develop directly into the adult phenotype. Metamorphosis is a dramatic change in physiology, behaviour, and life history, which results in an aquatic tadpole transforming into a terrestrial organism. This investigation utilized the metamorphic frog, Xenopus laevis, the African clawed frog, and the directly developing frog, Eleutherodactylus coqui, the coquí frog from Puerto Rico. Developing embryos and tadpoles of E. coqui and X. laevis were treated with several pharmaceutical agents that altered serotonin metabolism including: 5-HT inhibitor, serotonin precursors, 5-HT transporter inhibitor, and 5-HT 1A , 5-HT 2A/C , 5-HT 3 , 5-HT 4 receptor agonists and antagonists. Following treatment, embryos and tadpoles were analyzed using immunocytochemistry and high performance liquid chromatography to determine the effects of the altered serotonergic system on the onset and completion of metamorphosis as well as the progression of direct development. Results indicated that serotonin is important in the modulation of metamorphosis and that disruption of serotonin metabolism resulted in abnormal development of E. coqui. Although differences were noted between the two developmental pathways, it is concluded that serotonin is an essential neurochemical in both metamorphic and directly developing modes.The neurotrophin receptor TrkA plays critical roles in the nervous system by recruiting signaling molecules that activate pathways required for the growth and survival of neurons. Here, we report that APPL1, an adaptor protein implicated in endosomal signaling, is a TrkA-associated protein. APPL1 and TrkA co-immunoprecipitate in sympathetic neurons. We have identified two routes through which this association can occur. APPL1 was isolated as a binding partner for the TrkA-interacting protein GIPC1 from rat brain lysate by mass spectrometry. The PDZ domain of GIPC1 directly engaged the C-terminal sequence of APPL1. This interaction provides a means through which APPL1 may be recruited to TrkA. In addition, the APPL1 PTB domain bound to TrkA, indicating that APPL1 may associate with TrkA independently of GIPC1. Isolation of endosomal fractions by high-resolution centrifugation determined that APPL1, GIPC1 and phospho-TrkA are enriched in the same fractions. Reduction of APPL1 or GIPC1 protein levels suppressed nerve growth factor-dependent ERK and Akt activation and neurite outgrowth in PC12 cells. Together, these results indicate that GIPC1 and APPL1 play a role in TrkA function and suggest that a population of endosomes bearing a complex of APPL1, GIPC1 and activated TrkA may transmit NGF sig...