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

The neurotrophin gene family includes four structurally related protei ns 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 protect ion assay to analyse the developmental expression of NT-4 mRNA in the rat brain and in 12 different rat peripheral organs. In heart, liver a nd muscle plus skin NT-4 mRNA levels were maximal at embryonic day (E) E13 (the earliest time point tested), with reduced levels at later ti mes of development. In lung, kidney and thymus similar levels were see n from E13 to postnatal day (P) 1, with reduced levels in the adult. I n 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 ma ximal at E13 followed by a decrease around birth, after which the leve l increased. The postnatal increase of NT-4 mRNA was also seen in cere bral cortex and brain stem analysed separately, while in the hippocamp us similar levels were found from P1 to adulthood. NT-4 mRNA was detec ted in all ten adult rat brain regions analysed with only small region al variations, being highest in pons-medulla, hypothalamus, thalamus a nd cerebellum. Adult rat thymus, thyroid, muscle, lung and ovary conta ined higher levels of NT-4 mRNA than brain, while all other adult tiss ues showed similar or lower levels than in the brain. The highest leve l of NT-4 mRNA overall was found in P1 testis. For comparison, BDNF mR NA was analysed in the same tissues. The expression of BDNF mRNA was i n many cases different from that of NT-4 mRNA. The peak of NT-4 mRNA e xpression in several of the peripheral tissues coincided with the peak of naturally occurring neuronal cell death in peripheral ganglia. Thi s is consistent with the possibility that NT-4 acts as a target-derive d trophic factor in vivo. The widespread and increased expression of N T-4 mRNA during postnatal brain development could reflect a trophic ro le of NT-4 for central nervous system neurons. However, non-neuronal f unctions of NT-4 are also possible, particularly in male and female re productive tissues, where the NT-4 protein could function as a growth factor for immature germ cells.