During mammalian cortical development, neuronal precursors proliferate
within ventricular regions then migrate to their target destinations
in the cortical plate, where they organize into layers. In the rat, mo
st cortical neuronal migration occurs during the final week of gestati
on (Bayer et al., 1991; Jacobson, 1991). At this time (E15-E21), rever
se transcriptase-polymerase chain reaction demonstrated that cortical
homogenates contain mRNA encoding brain derived neurotrophic factor (B
DNF) and the catalytic form of its high-affinity receptor, TrkB. Immun
ocytochemistry and in situ hybridization of sections revealed that the
catalytic TrkB receptors predominantly localize to regions containing
migratory cells. Many TrkB+ cells exhibited the classic morphology of
migrating neurons, suggesting that TrkB ligands play a role in cortic
al neuronal migration. We analysed whether TrkB ligands influence the
motility of embryonic cortical cells (from E15-E21) using a quantitati
ve in vitro chemotaxis assay. High-affinity TrkB ligands (BDNF and NT4
/5) stimulated chemotaxis (directed migration) of embryonic neurons at
concentrations ranging from 1 to 100 ng/ml. NT-3, a low-affinity TrkB
ligand, only stimulated significant migration at high concentrations
(greater than or equal to 100 ng/ml). Peak migration to BDNF was obser
ved at gestational day 18 (E18). BDNF-induced chemotaxis was blocked b
y either tyrosine kinase inhibitor, K252a, or the Ca2+-chelator, BAPTA
-AM, suggesting that BDNF-induces motility via autophosphorylation of
TrkB receptor proteins and involves Ca2+-dependent mechanisms. BDNF-st
imulation of increased cytosolic Ca2+ was confirmed with optical recor
dings of E18 cortical cells loaded with Ca2+ indicator dye. Thus, sign
al transduction through the TrkB receptor complex directs neuronal mig
ration, suggesting that, in vivo, BDNF exerts chemotropic effects that
are critical to morphogenesis of the cortex.