Involvement of leukemia inhibitory factor and nerve growth factor in the development of dorsal root ganglion neurons

Abstract

Leukemia inhibitory factor (LIF) was recently shown to stimulate the generation of sensory neurons from the murine neural crest in vitro. Here, we examine the respective activities of LIF and nerve growth factor (NGF) throughout the embryonic development of sensory neurons in dorsal root ganglia (DRG) and neural crest. In cultures of embryonic day 12 (E12) DRG, which contain sensory neuron precursor cells, a combination of both LIF and NGF are required for the differentiation of mature sensory neurons from their neurofilament negative (NF-) precursors. The primary differentiation step from NF- cell to NF+ immature neuron is promoted by LIF, whereas the survival and further maturation of the newly differentiated neurons depends on NGF. In cultures of sensory neurons isolated at the time of target innervation (E14 and E15 DRG), the survival of the majority of the neurons is dependent on NGF. However, LIF acts as a survival agent for a discrete population of NGF non-responsive neurons. From E16, the number of neurons maintained by LIF increases to > 90% by birth. Consistent with the in vitro observations, LIF mRNA could be detected at early developmental stages (E12-E13), within the spinal column and DRG as well as the limbs and, later (after E15), in areas of sensory innervation (skin, limbs, feet and gut). This supports the idea that LIF, as well as NGF, may regulate sensory development in vivo.