WIDESPREAD AND DEVELOPMENTALLY-REGULATED EXPRESSION OF NEUROTROPHIN-4 MESSENGER-RNA IN RAT-BRAIN AND PERIPHERAL-TISSUES

The neurotrophin gene family includes four structurally related proteins with neurotrophic activities. Two of them, nerve growth factor and brain-derived neurotrophic factor (BDNF), have been studied in detail and information has recently emerged on the expression and function of the third member, neurotrophin-3. In contrast, little information is available on neurotrophin-4 (NT-4), the most recently isolated member of this family. In this report we have used a sensitive RNAase protection assay to analyse the developmental expression of NT-4 mRNA in the rat brain and in 12 different rat peripheral organs. In heart, liver and muscle plus skin NT-4 mRNA levels were maximal at embryonic day (E) E13 (the earliest time point tested), with reduced levels at later times of development. In lung, kidney and thymus similar levels were seen from E13 to postnatal day (P) 1, with reduced levels in the adult. In testis, ovary and salivary gland NT-4 mRNA was detected at E16 with a peak shortly after birth. During brain development, NT-4 mRNA was maximal at E13 followed by a decrease around birth, after which the level increased. The postnatal increase of NT-4 mRNA was also seen in cerebral cortex and brain stem analysed separately, while in the hippocampus similar levels were found from P1 to adulthood. NT-4 mRNA was detected in all ten adult rat brain regions analysed with only small regional variations, being highest in pons-medulla, hypothalamus, thalamus and cerebellum. Adult rat thymus, thyroid, muscle, lung and ovary contained higher levels of NT-4 mRNA than brain, while all other adult tissues showed similar or lower levels than in the brain. The highest level of NT-4 mRNA overall was found in P1 testis. For comparison, BDNF mRNA was analysed in the same tissues. The expression of BDNF mRNA was in many cases different from that of NT-4 mRNA. The peak of NT-4 mRNA expression in several of the peripheral tissues coincided with the peak of naturally occurring neuronal cell death in peripheral ganglia. This is consistent with the possibility that NT-4 acts as a target-derived trophic factor in vivo. The widespread and increased expression of NT-4 mRNA during postnatal brain development could reflect a trophic role of NT-4 for central nervous system neurons. However, non-neuronal functions of NT-4 are also possible, particularly in male and female reproductive tissues, where the NT-4 protein could function as a growth factor for immature germ cells.