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Regulation of dendritic development by BDNF requires activation of CRTC1 by glutamate.

ABSTRACT: Dendritic growth is essential for the establishment of a functional nervous system. Among extrinsic signals that control dendritic development, substantial evidence indicates that BDNF regulates dendritic morphology. However, little is known about the underlying mechanisms by which BDNF controls dendritic growth. In this study, we show that the MAPK signaling pathway and the transcription factor cAMP response element-binding protein (CREB) mediate the effects of BDNF on dendritic length and complexity. However, phosphorylation of CREB alone is not sufficient for the stimulation of dendritic growth by BDNF. Thus, using a mutant form of CREB unable to bind CREB-regulated transcription coactivator (CRTC1), we demonstrate that this effect also requires a functional interaction between CREB and CRTC1. Moreover, inhibition of CRTC1 expression by shRNA-mediated knockdown abolished BDNF-induced dendritic growth of cortical neurons. Interestingly, we found that nuclear translocation of CRTC1 results from activation of NMDA receptors by glutamate, a process that is essential for the effects of BDNF on dendritic development. Together, these data identify a previously unrecognized mechanism by which CREB and the coactivator CRTC1 mediate the effects of BDNF on dendritic growth.

SUBMITTER: Finsterwald C

PROVIDER: S-EPMC2937884 | biostudies-other | 2010 Sep

REPOSITORIES: biostudies-other

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Regulation of dendritic development by BDNF requires activation of CRTC1 by glutamate.

Finsterwald Charles C Fiumelli Hubert H Cardinaux Jean-René JR Martin Jean-Luc JL

The Journal of biological chemistry 20100716 37

Dendritic growth is essential for the establishment of a functional nervous system. Among extrinsic signals that control dendritic development, substantial evidence indicates that BDNF regulates dendritic morphology. However, little is known about the underlying mechanisms by which BDNF controls dendritic growth. In this study, we show that the MAPK signaling pathway and the transcription factor cAMP response element-binding protein (CREB) mediate the effects of BDNF on dendritic length and comp ...[more]

PMID: 20639200

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Project description:Retinal ganglion cells (RGCs) have a wide variety of dendritic architectures, which are critical for the formation of their function-specific synaptic circuitry. The developmental regulation of the dendrites of RGCs is thought to be subtype dependent. The purpose of this study is to characterize the dendritic development of a genetically identified RGC subtype, JamB RGCs (J-RGCs), and the roles of glutamate receptor activity on the dendritic development of these cells. We show that the dendrites of J-RGCs are strictly ramified in the outer portion of the inner plexiform layer (IPL) of the retina at the age of postnatal day 8 (P8), mimicking the ramification pattern of adults. However, several other important features of dendrites undergo substantial developmental refinement after P8. From P8 to P13, the dendritic development of J-RGCs is characterized by a dramatic increase of dendritic length and the size of the dendritic field. After eye opening, the dendritic development of J-RGCs is characterized by a tremendous decrease of the number of dendritic protrusions (spine-like structures) and a consolidation of the size of the dendritic field. To determine whether the dendritic development of J-RGCs is regulated by glutamatergic activity, we conditionally knocked out the expression of an obligatory subunit of N-methyl-D-aspartate receptors (NMDARs), NR1 (Grin1), in J-RGCs. We found that J-RGCs with the NMDAR mutation have decreased dendrite outgrowth and dendritic field expansion but increased number of dendritic protrusions before eye opening. To determine if visual experience regulates the development of J-RGC dendrites, we raised the mice in complete darkness after birth. Light deprivation prevented the decrease in the number of dendritic protrusions and the consolidation of the dendritic field of wild type (WT) mice after eye opening. However, light deprivation has no additional effect on the number of dendritic protrusions or the size of the dendritic field of J-RGCs with NMDAR mutation. Together, these results revealed the roles of light stimulation and NMDAR activity on the dendritic development of J-RGCs.

Dataset Information

Regulation of dendritic development by BDNF requires activation of CRTC1 by glutamate.

Publications

Regulation of dendritic development by BDNF requires activation of CRTC1 by glutamate.

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