AXONAL GROWTH AND FASCICULATION LINKED TO DIFFERENTIAL EXPRESSION OF BDNF AND NT3 RECEPTORS IN DEVELOPING CEREBELLAR GRANULE CELLS

In the developing cerebellum, young granule neurons in the external ge rminal layer respond preferentially to BDNF, while mature neurons with in the inner portion of the cerebellum respond preferentially to NT3. Here we show that this anatomic distinction reflects a developmentally regulated switch at the level of neurotrophin receptor gene expressio n. The salient feature of the developmental switch is a change in the ratio of mRNA transcripts encoding functional BDNF and NT3 receptor ty rosine kinases. The ratio of the BDNF receptor trkB to the NT3 recepto r trkC reverses from 5:1 in neonatal cerebellum to 1:3 in adult cerebe llum. TrkB and TrkC are closely related transmembrane tyrosine protein kinases. However, activation of BDNF and NT3 receptors in cerebellar granule neurons do not give equivalent biological responses. In aggreg ate cell culture and single cell assays, BDNF enhances axonal outgrowt h of early granule cells by influencing neurite elongation. In contras t, NT3 alters the morphology of outgrowth. Collectively, these finding s suggest that regulation of neurotrophin receptors during cerebellar development is important for the timing and morphology of axonal growt h.