Cell-intrinsic drivers of dendrite morphogenesis

Abstract

The proper formation and morphogenesis of dendrites is fundamental to the establishment of neural circuits in the brain. Following cell cycle exit and migration, neurons undergo organized stages of dendrite morphogenesis, which include dendritic arbor growth and elaboration followed by retraction and pruning. Although these developmental stages were characterized over a century ago, molecular regulators of dendrite morphogenesis have only recently been defined. In particular, studies in Drosophila and mammalian neurons have identified numerous cell-intrinsic drivers of dendrite morphogenesis that include transcriptional regulators, cytoskeletal and motor proteins, secretory and endocytic pathways, cell cycle-regulated ubiquitin ligases, and components of other signaling cascades. Here, we review cell-intrinsic drivers of dendrite patterning and discuss how the characterization of such crucial regulators advances our understanding of normal brain development and pathogenesis of diverse cognitive disorders.

Keywords: Cell-intrinsic driver; Dendrite development; Dendrite morphogenesis; Dendrite patterning; Transcription factor; Ubiquitin ligases.

Fig. 1.

Critical stages of dendrite morphogenesis in mammalian neurons. The morphogenesis of granule neuron dendrites in the cerebellar cortex, like that of dendrites in other areas of the brain and in other organisms, occurs via distinct stages mediated by a variety of molecular regulators. After exiting the cell cycle, neural progenitors undergo polarization, whereby an axon is specified and subsequently extends, and this is followed by the specification of additional processes as dendrites. Dendrite morphogenesis then begins with dendrite growth and branching. Exuberant dendrite arbors are then pruned with the elimination of some processes but not others, yielding the dendrites that will persist after development. These remaining dendrites undergo a process of differentiation and maturation, whereby they develop specialized structures suited to the formation of synapses and contact with axons. Although the exact order of these steps and their timing varies between individual neuronal types and organisms, these fundamental steps are generally conserved. The image shown depicts granule neurons of the rat cerebellar cortex at distinct stages of dendrite development as initially drawn and characterized by Ramón y Cajal (Ramón y Cajal, 1995). In the last stage, specialized structures for synaptic input known as dendritic claws are pictured as cup-like extensions at the ends of the dendrites.

Fig. 2.

Calcium-mediated regulation of dendrite morphogenesis. Calcium-regulated control occurs throughout dendrite morphogenesis - during growth and elaboration as well as during dendrite pruning and retraction. (A) Neuronal depolarization with subsequent calcium entry via voltage-sensitive calcium channels (VSCCs) or NMDA receptors (NMDARs) triggers the activation of calcium/calmodulin-dependent kinase (CaMK) family members, thereby directing transcription factor activity in the nucleus. CREB functions downstream of CaMKIγ or CaMKIV, while the transcription factor NeuroD is phosphorylated and activated by CaMKIIα. Other transcriptional regulators such as CBP bind to CREB and influence transcription. At the level of chromatin, the chromatin remodeling complex nBAF plays a role in regulating activity-dependent dendrite growth. CREST binds to the nBAF complex and, in turn, controls gene expression. Together, these diverse mechanisms provide complex, yet tightly regulated, control of gene expression relevant for dendrite growth, including Bdnf, Wnt2 and Cpg15 (Nrn1). (B) During later stages of dendrite development, calcium regulates ubiquitin signaling at the centrosome to drive dendrite retraction and pruning. Calcium influx via the membrane channel TRPC5 activates CaMKIIβ, which phosphorylates and inhibits the major ubiquitin ligase Cdc20-APC at the centrosome. As a result, the Cdc20-APC substrate Id1 accumulates at the centrosome leading to dendrite retraction and pruning.

Fig. 3.

A summary of the key cell-intrinsic regulators of distinct stages of dendrite morphogenesis. Individual proteins or their signaling cassettes involved at each stage of dendrite morphogenesis are indicated, as described in the main text. In cases in which a given factor has opposing effects on two different populations of neurons, the neuron type is listed in parentheses.