EGF transactivation of Trk receptors regulates the migration of newborn cortical neurons

Abstract

The development of neuronal networks in the neocortex depends on control mechanisms for mitosis and migration that allow newborn neurons to find their accurate position. Multiple mitogens, neurotrophic factors, guidance molecules and their corresponding receptors are involved in this process, but the mechanisms by which these signals are integrated are only poorly understood. We found that TrkB and TrkC, the receptors for brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), are activated by epidermal growth factor receptor (EGFR) signaling rather than by BDNF or NT-3 in embryonic mouse cortical precursor cells. This transactivation event regulated migration of early neuronal cells to their final position in the developing cortex. Transactivation by EGF led to membrane translocation of TrkB, promoting its signaling responsiveness. Our results provide genetic evidence that TrkB and TrkC activation in early cortical neurons do not depend on BDNF and NT-3, but instead on transactivation by EGFR signaling.

BDNF: An Oncogene or Tumor Suppressor?

“…Brain-derived neurotrophic factor (BDNF) has been widely implicated in the development, migration, differentiation and survival of fetal neurons (1). BDNF binds its conjugate receptor, TrkB, and initiates a signaling cascade marked by increased activity of the pi3K/Akt growth pathway leading to production of pro-migratory, antiapoptotic and pro-survival proteins (2,3).…”

“…BDNF binds its conjugate receptor, TrkB, and initiates a signaling cascade marked by increased activity of the pi3K/Akt growth pathway leading to production of pro-migratory, antiapoptotic and pro-survival proteins (2,3). it has been uniquely demonstrated that activation of the BDNF signaling pathway transactivates the epidermal growth factor receptor (EGFR) even in the absence of the endogenous EGF ligand (1). As a consequence, this augments the activity of phospholipase-c-y (pLcy) and of downstream targets such as various protein kinase c isoforms.…”

Ntf3 acts downstream of Sip1 in cortical postmitotic neurons to control progenitor cell fate through feedback signaling

“…Another possibility is that the receptors for Ntf3 (Trks) are also activated by alternate pathways in the developing cortex (Lee et al, 2002). For example, recent work has shown that EGFR can transactivate both TrkB and TrkC (Ernfors et al, 1994;Puehringer et al, 2013). Interestingly, Bdnf and Ntf3 have opposing functions in laminar fate specification (Fukumitsu et al, 2006).…”

Loss of BDNF or its receptors in three mouse models has unpredictable consequences for anxiety and fear acquisition

“…Also, there is increasing evidence of TrkB activation in a manner that is independent of neurotrophins. Thus, a recent study reported that cortical development requires neurotrophin-independent TrkB transactivation (Puehringer et al 2013).…”