Protocadherins branch out: Multiple roles in dendrite development

Figures & data

Figure 1. Clustered and Non-Clustered Protocadherins. Schematic domain structures of the clustered (α-, β-, and γ-) Pcdhs, and of the δ1- and δ2- non-clustered Pcdhs. Domains as indicated by legend; double horizontal line represents the plasma membrane. The domain structure of a classical cadherin is shown for comparison. A summary of known dendritic functions appears above each schematic.

Figure 2. Atypical Cadherins. Schematic domain structures of Flamingo, Celsr, and Fat atypical cadherins. Domains as indicated by legend; double horizontal line represents the plasma membrane. A summary of known dendritic functions appears above each schematic. Because Fat proteins have too many cadherin repeats to easily depict in a reasonably-sized figure, the double-diagonal lines indicate continuation of cadherin repeats between the 6th and 29th.

Table 1. Clustered Protocadherin Dendritic Roles

Gene Symbol	Name	Reported Dendritic Role	References
PCDHA	α-Protocadherins	PCDHA knockout results in decreased dendrite arborization and spine loss in hippocampal neurons, in vivo and in vitro. This arborization defect was dependent on PYK2/Rho/Rac pathway as PYK2 knockdown and constitutively active Rac1 rescued the phenotype while PYK2 overexpression reduced arbors.	Suo, et al., 2012
PCDHB	β-Protocadherins	β16 and β22 localizes postsynaptically in retinal and cerebellar neurons. As of yet, no functional data published.	Junghans, et al., 2008; Puller and Haverkamp, 2010
PCDHG	γ-Protocadherins	γ-Pcdhs are found at dendro-dendritic and axo-dendritic appositions, with significant portions retained intracellularly in compartments rich in COPII and ERGIC vesicles. γ-Pcdh staining colocalizes with both calnexin (ER protein) and COPII puncta, and is found in tubulovesicular structures in dendrites.	Fernandez-Monreal et al., 2009, 2010
		γ-Pcdh knockout reduces dendritic arborization in apical and basal dendrites of cortical layer V pyramidal neurons. γ-Pcdh inhibition of a FAK/PKC/MARCKS pathway allows for normal arborization, as γ-Pcdh loss results in aberrant upregulation of this pathway.	Garrett et al., 2012
		γ-Pcdh knockout in retinal starburst amacrine cells (SACs) and cerebellar Purkinje cells leads to aberrant self-crossing of dendrites isoneuronally. Single γ-Pcdh isoform expression rescues this self-avoidance defect, but leads to aberrant heteroneuronal avoidance of SAC dendrites.	Lefebvre, et al., 2012
		γ-Pcdh knockdown of hippocampal neurons in vitro results in reduced dendritic arborization as well as activation of PYK2 and FAK and increased Rho inhibition. Constitutively active Rac1 rescues this phenotype.	Suo et al., 2012
		γ-Pcdh knockout in individual subventricular zone progenitor cells causes a reduction in dendritic arborization and loss of dendritic spines in olfactory bulb granule cells derived from these cells.	Ledderose et al., 2013
		γ-Pcdh-mediated Purkinje cell self-avoidance was shown to be genetically independent of similar slit/robo-mediated self-avoidance.	Gibson, et al., 2014
PCDHA, B, and G	All clustered Protocadherins (and/or possibly other genes affected by manipulation)	Dnmt3b methylation of PCDHA and selected PcdhB/G promoters determines expression frequency of α-Pcdhs within Purkinje neurons. Cell specific knockout of Dnmt3b decreases methylation and increases frequency of expression leading to self-avoidance defects in Purkinje cell dendritic arbors. May be due to non-Pcdh gene disruption as well.	Toyoda, et al., 2014
		CTCF knockout cortex exhibited decreased PCDHA, PCDHB, and PCDHG expression, as well as a reduction of arborization of both apical and basal dendrites. Dendritic spines were also reduced in these neurons, and hippocampal neurons also had reduced dendritic arbors. May be due to non-Pcdh gene disruption as well.	Hirayama, et al., 2012

Table 2. Nonclustered Protocadherin Dendritic Roles

Gene Symbol	Name	Reported Dendritic Role	References
	δ1 (Delta 1) family
PCDH7 (NFPC)	Protocadherin 7, NF-protocadherin (Xenopus)	Promotes retinal ganglion cell dendrite arborization, possibly through TAF1.	Piper, et al., 2008
	δ2 (Delta 2) family
PCDH8	Protocadherin 8, Arcadlin (mammals), paraxial protocadherin (Xenopus)	Pcdh8 causes a decrease in spine number by activation of a MAPK pathway resulting in Pcdh8/N-cadherin endocytosis. Consequently, neurons cultured from Pcdh8 knockout mice have increased dendritic spines, but only when in the presence of N-cadherin.	Yasuda, et al., 2007
PCDH10	Protocadherin 10, OL-protocadherin	Pcdh10 knockdown prevented MEF2-induced synapse elimination. Pcdh10 is necessary for ubiquitination and proteosomal degradation of PSD-95, leading to spine loss.	Tsai, et al., 2012

Table 3. Atypical Cadherin Dendritic Roles

Gene Symbol	Name	Reported Dendritic Role	References
FAT3	Fat3	In retinal amacrine cells, Fat3 regulates dendritic pruning. Fat3 knockout mice have defective pruning and exhibit a second, aberrant dendritic arbor projecting to an inappropriate layer.	Deans, et al., 2011
Fmi	Flamingo, starry night	Fmi is required for the extension of dorsal dendrites and the repulsion between dendrites of homologous multiple dendrite (md) sensory neurons.	Gao, et al., 1999,2000; Grueber et al., 2002; Sweeney, et al., 2002; Kimura, et al., 2006
		Fmi does not act through frizzled to regulate dendritic tiling. Fmi mutants showed overextension into adjacent dendrites potentially mixing their dendritic fields.
		Fmi controls the timing and extent of dendrite arborization of md neurons.
		Fmi has a dual molecular function that intially controls dendrite extension followed by avoidance between dendritiC-terminals.
		Dendrites of the drosophila mushroom body neurons (CNS) show overextension phenotypes similar to that of md neurons (PNS).	Reuter, et al., 2003
		Fmi overexpression enhances the negative regulation of dendrite outgrowth mediated by Gogo.	Hakeda-Suzuki, et al., 2011, 2013
		Dendritic self-avoidance of Drosophila sensory neurons requires fmi and Espinas.	Matsubara, et al., 2011
Celsr2	Cadherin EGF LAG 7-pass G-type receptor (Celsr) 2	RNAi knockdown of Celsr2 leads to reduced complexity of dendritic arbors of cortical pyramidal neurons and cerebellar Purkinje neurons.	Shima, et al., 2004
		RNAi knockdown indicates that Celsr2 normally functions to enhance neurite outgrowth. In vitro gene silencing and coculture assays showed reduced neurite outgrowth and dendrite arborization.	Shima, et al., 2007
Celsr3	Cadherin EGF LAG 7-pass G-type receptor (Celsr) 3	RNAi knockdown indicates that Celsr3 normally functions to suppress neurite growth. In vitro gene silencing and coculture assays showed increased neurite outgrowth and dendrite arborization. The opposite effects of Celsr 2 and 3 are controlled by a single amino acid difference in a cytoplasmic loop.	Shima, et al., 2007