The dynamic ubiquitin ligase duo: Cdh1-APC and Cdc20-APC regulate neuronal morphogenesis and connectivity

Abstract

The proper development and patterning of axons, dendrites, and synapses is essential for the establishment of accurate neuronal circuits in the brain. A major goal in neurobiology is to identify the mechanisms and principles that govern these fundamental developmental events of neuronal circuit formation. In recent years, exciting new studies have suggested that ubiquitin signaling pathways may play crucial roles in the control of neuronal connectivity. Among E3 ubiquitin ligases, Cdh1-anaphase promoting complex (Cdh1-APC) and Cdc20-APC have emerged as key regulators of diverse aspects of neuronal connectivity, from axon and dendrite morphogenesis to synapse differentiation and remodeling.

Figure 1. The structure of the APC

The APC is composed of at least 12 core subunits including the Cul1-related scaffold protein APC2 and the RING finger protein APC11 shown in red. The APC associates with one of two co-activators, Cdh1 or Cdc20 (shown in yellow), which confer substrate specificity and stimulate the ubiquitin ligase activity of the APC. The tetratricopeptide repeat (TPR) containing core subunits Cdc27, Cdc23, and Cdc16 (shown in blue) act as a scaffold to promote the interaction of Cdh1 and Cdc20 with the APC.

Figure 2. Cdh1-APC and Cdc20-APC govern the spatially distinct processes of axon and dendrite morphogenesis

Cdh1-APC operates in the nucleus to regulate axon growth and patterning. Cdh1-APC restricts axon growth by targeting the transcriptional regulators SnoN and Id2 for degradation. SnoN and Id2 regulate the transcription of target genes enriched at the axon growth cone including Ccd1 and NgR. The TGFβ/Smad2 and Cdk signaling pathways converge upon Cdh1-APC to regulate axon morphogenesis. Upon activation by TGFβ, Smad2 interacts with Cdh1 and induces Cdh1-APC-dependent ubiquitination of SnoN. Conversely, Cdk inhibits Cdh1-APC activity by phosphorylating Cdh1 at nine conserved sites, leading to the accumulation of an inactive form of Cdh1 in the cytoplasm. Cdc20-APC operates at the centrosome to drive dendrite growth and elaboration. Polyubiquitination of Cdc20 enhances Cdc20-APC activity and dendrite growth. HDAC6 promotes the polyubiquitination of Cdc20, while USP44 deubiquitinates Cdc20. The centrosomally-localized protein Id1 represents a substrate of neuronal Cdc20-APC that inhibits dendrite growth.

Figure 3. Cdh1-APC regulates synapse size and glutamatergic neurotransmission in invertebrates

Cdh1 and core subunits of the APC are localized at the presynaptic bouton at the Drosophila NMJ. Presynaptic APC controls the abundance of the active zone protein Liprinα and restricts the number of presynaptic boutons contacting the postsynaptic muscle cell. On the postsynaptic side, Cdh1-APC limits the expression of glutamate receptor subunits in worms and flies. The mechanism of APC regulation of glutamate receptors awaits further study.

Figure 4. Cdc20-APC drives presynaptic differentiation in mammalian brain neurons

Top: during early axon differentiation, NeuroD2-dependent transcription of the target gene Cplx2 suppresses presynaptic differentiation. Bottom: As Cdc20 expression increases with neuronal maturation, Cdc20-APC targets NeuroD2 protein for degradation and thereby promotes the formation of functional presynaptic sites. Figure adapted from [43••].