Ca2+, CREB and krüppel: A novel KLF7-binding element conserved in mouse and human TRKB promoters is required for CREB-dependent transcription

Brain-derived neurotrophic factor (BDNF) signaling through its receptor, trkB, is essential for the proper development and function of the nervous system. Here we identify a novel regulatory element designated TCaRE3 (TRKB Ca2+ response element 3) required for CREB-dependent TRKB transcription in neurons. TCaRE3-inactivating mutations abolished both Ca2+- and cAMP-stimulated TRKB expression, despite the presence of upstream CREs. TCaRE3 mutations also reduced basal expression by at least 80%. Electrophoretic mobility shift assays revealed the presence of a neuronal nuclear factor able to bind TCaRE3 in a sequence-specific manner and we have identified krüppel-like factor 7 (KLF7) as a candidate TCaRE3 transcription factor. Importantly, despite limited overall sequence homology between the promoter regions of the human and mouse TRKB genes, TCaRE3 exhibits 100% sequence identity. Mutation analysis of the human TRKB promoter region demonstrated that the role of TCaRE3 is also conserved, suggesting that the functional interaction between CREB bound to the CREs and KLF7 bound to TCaRE3 is essential for the proper regulation of TRKB in neurons.