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For a given cell type, particular extracellular signals generate characteristic patterns of activity in intracellular signalling networks that lead to distinctive cell-type specific responses. Here, we report the first known occurrence of a developmental switch in the intracellular signalling network required for an identical cellular response to the same extracellular signal in the same cell type. We show that although NF-kappaB signalling is required for BDNF-promoted neurite growth from both foetal and postnatal mouse sensory neurons, there is a developmental switch between these stages in the NF-kappaB activation mechanism and the phosphorylation status of the p65 NF-kappaB subunit required for neurite growth. Shortly before birth, BDNF activates NF-kappaB by an atypical mechanism that involves tyrosine phosphorylation of IkappaBalpha by Src family kinases, and dephosphorylates p65 at serine 536. Immediately after birth, BDNF-independent constitutive activation of NF-kappaB signalling by serine phosphorylation of IkappaBalpha and constitutive dephosphorylation of p65 at serine 536 are required for BDNF-promoted neurite growth. This abrupt developmental switch in NF-kappaB signalling in a highly differentiated cell type illustrates an unsuspected plasticity in signalling networks in the generation of identical cellular responses to the same extracellular signal.

Developmental switch in NF-κB signalling required for neurite growth