Lrig1 is a cell-intrinsic modulator of hippocampal dendrite complexity and BDNF signaling

Abstract

Even though many extracellular factors have been identified as promoters of general dendritic growth and branching, little is known about the cell-intrinsic modulators that allow neurons to sculpt distinctive patterns of dendrite arborization. Here, we identify Lrig1, a nervous system-enriched LRR protein, as a key physiological regulator of dendrite complexity of hippocampal pyramidal neurons. Lrig1-deficient mice display morphological changes in proximal dendrite arborization and defects in social interaction. Specifically, knockdown of Lrig1 enhances both primary dendrite formation and proximal dendritic branching of hippocampal neurons, two phenotypes that resemble the effect of BDNF on these neurons. In addition, we show that Lrig1 physically interacts with TrkB and attenuates BDNF signaling. Gain and loss of function assays indicate that Lrig1 restricts BDNF-induced dendrite morphology. Together, our findings reveal a novel and essential role of Lrig1 in regulating morphogenic events that shape the hippocampal circuits and establish that the assembly of TrkB with Lrig1 represents a key mechanism for understanding how specific neuronal populations expand the repertoire of responses to BDNF during brain development. Synopsis Lrig1 is a novel regulator of dendritogenesis and apical dendrite branching of CA1-CA3 pyramidal hippocampal neurons in vivo, acting as an endogenous inhibitor of neurotrophin-induced proximal dendrite arborization of pyramidal hippocampal neurons. Lrig1 is a physiological regulator of hippocampal dendrite development. Lrig1 is required for proper apical dendrite arborization of CA1-CA3 pyramidal neurons and social behavior. Lrig1 controls TrkB signaling and dendrite development induced by BDNF. Lrig1 regulates dendritogenesis and apical dendrite branching of CA1-CA3 pyramidal hippocampal neurons in vivo, acting as an endogenous inhibitor of neurotrophin-induced proximal dendrite arborization of pyramidal hippocampal neurons.