The anatomical and functional data we present suggest that ™-catenin is required for the maintenance of dendrites and dendritic spines in mature neocortex, but does not appear to be required for the initial establishment of normal dendrite complexity and length and spine density in vivo
. This conclusion is somewhat at odds with recent reports documenting the necessity of δ-catenin for normal dendritic growth and spine formation of cultured hippocampal neurons (Arikkath et al., 2008
; Elia et al., 2006
; Kim et al., 2008
). Because all of the data we present here documents changes in mature cortex in vivo
, we can make no statement on whether our conclusions can be applied to developing hippocampus. Our results also support a view in which proper cortical function, and by extension, cognitive function, depends on the maintenance of the full complexity of each neuron's dendritic tree and the maintenance of the synaptic input to these dendrites.
Changes in neuronal dendritic morphology are induced by changes in cytoskeletal dynamics. The Rho family of small GTPases are highly conserved regulators of the cytoskeleton (Hall, 1998) and in neurons are important intermediates of extracellular stimuli and dynamic changes in neuronal morphology and connectivity (Elia et al., 2006
; Leemhuis et. al., 2004; Martinez et. al., 2003
; Nakayama et. al., 2000; Parrish et. al., 2007). δ-catenin in vitro
can promote actin dependent dendritic branching by regulating Rho activity (Abu-Elneel et al., 2008; Martinez et al., 2003
; Kim et al., 2008
; Kim et al., 2008b
). Activation of Rho results in a rapid loss of distal but not primary processes in hippocampal neurons in vitro
(Nakayama et al., 2000; Kim et al., 2002
). δ-catenin mediates Rho activity through an inhibitory interaction with the Rho activator, p190RhoGEF (Abu-Elneel et al., 2008; Kim et al., 2008
; Kim et al., 2008b
). The loss of distal, but not primary dendritic branches we report here is similar to the loss observed with activation of Rho.
δ-catenin likely regulates spine maintenance and stability through its interactions with other proteins in the synaptic adherens junction. Loss of δ-catenin results in decreased protein levels of α-catenin, β-catenin, and N-cadherin (Benson et al., 1998
; Fannon & Coleman 1996
; Israely et al., 2004
). P120 catenin family members, including δ-catenin, stabilize adherens junction components in vitro
(Davis et al., 2003). Although in vivo
data from δ-catenin mutant mice is consistent with a functional role for δ-catenin in stabilizing synaptic adherens junction components, it remains unclear whether the observed reduction of these components in vivo
is caused by decreased stability or simply a decrease in the number of dendritic spines. Despite these uncertainties, the altered spine dynamics observed in the δ-catenin mutant mice are consistent with both increased activation of Rho in mature neurons and down regulation of adherens junction components (Nakayama et al., 2000; Tashiro et al., 2000; Govek et al., 2004; Takeichi et al., 2007; Bozdagi et al., 2004; Bozdagi et al., 2000; Abe et al., 2004; Okamura et al., 2004; Tang et al., 1998; Inoue and Sanes, 1997
; Iwai et al., 2002; Tai CY et al., 2007).
Notably, our data do not support a role for δ-catenin in the formation of new dendritic spines. The rate of spine growth was unaffected in mutant mice, and the cumulative distribution of spine volumes along retracting dendrites showed no change in the fraction of small volume spines, which have very short lifetimes and have typically grow in the 1-3 day period preceding the image (Holtmaat et al., 2005
; Knott et al., 2006
; Trachtenberg et al., 2002
The observed progressive decline in dendritic length, complexity, and spine density in the δ-catenin mutant mice decreases the connectivity of neural circuits. This likely underlies the loss of cortical responsiveness to sensory and direct stimulation, and impairs the integration and processing of information in these circuits (Hausser et al., 2000). Loss or abnormal connectivity in the cortex has long been suggested to underlie mental retardation (Kaufmann et al., 2000). In humans, δ-catenin is localized on chromosome 5p15.2, the critical region for the severe mental retardation syndrome, Cri-du-Chat (CDCS). Breakpoint analysis in patients with 5p terminal deletions indicates that the severity of mental retardation correlated with hemizygous loss of the δ-catenin gene (Medina et al., 2000
). It is not clear how dendrites are compromised in CDCS, and attributing any dendritic anomalies to δ-catenin loss is problematic – semaphorin F, a regulator of axon pathfinding, is also localized to the same chromosomal region. However, our studies suggest that CDCS, and other forms of mental retardation could result from a progressive degeneration of neural connectivity rather than, or in addition to a deficit of circuit establishment.
Supporting this view, δ-catenin mutant mice display severe impairments in hippocampal dependent learning paradigms, including the Morris water maze and contextual fear conditioning (Israely et al., 2004
). This impaired cognitive function likely has a cortical component as well. We observed progressive functional impairments in cortical visual information processing that precede the timing of the behavioral studies in Israely (2004)
. It is likely that the degraded sensory processing resulting from dendritic retraction contributes to the observed spatial learning deficit in the delta catenin mutant mice. In particular, the Morris water maze relies on the mouse using distal extramaze visuo-spatial cues to orient itself and locate the hidden platform. To control for visual ability, the visible platform task is used. One problem with this setup is that the intramaze visual cues that signal the platform location are closer than the extramaze visual cues used in the hidden version of the task. A reduction in visual acuity would impair navigation based on the more distant visual cues used in the hidden version of the task. Thus, the visual impairment we observe would accentuate the magnitude of the spatial the learning deficit.
These results have additional implications in the pathogenesis of Alzheimer's disease. δ-catenin was first identified through its interaction with the loop domain of Presenilin-1 (PS1), a region containing a concentration of Familial Alzheimer's Disease (FAD)-linked point mutations (Zhou et al., 1997
). FAD is a disorder characterized in its earliest stages by cognitive decline, followed by the accumulation of extracellular amyloid plaques, neurofibrillary tangles, degeneration of neuronal architecture, and eventual neuronal loss (Selkoe, 2001). Notably, over-expression of wild type PS1 inhibits δ-catenin induced cellular branching and promotes δ-catenin processing and turnover (Kim et al., 2006
), and FAD mutations in the PS1 loop domain, M146V and L286V, accelerate the degradation of δ-catenin (Kim et al., 2006
). The progressive retraction of dendrites and loss of presumptive synapses in the δ-catenin mutant mice bears strong similarity to the pathogenesis of FAD. It is possible that δ-catenin degradation is enhanced in FAD, resulting in a progressive decline in protein levels. This, in turn, may contribute to the observed morphological and pathological changes that occur in the pathogenesis of FAD.
Taken together, this work indicates a novel role for δ-catenin in the maintenance of neural function by regulating the stability of dendritic and synaptic structures in vivo. Our data lends support to the importance of the maintenance of proper connectivity in cognitive function and provides insight into novel mechanisms that may underlie severe mental retardation and diseases of the nervous system.