30996
Altered Expression of Cadherins Suggests Their Potential Roles in Brain Development and Autism
Multiple members of the cadherin superfamily have been strongly implicated in autism. The cadherin superfamily contains more than one hundred cell adhesion molecules. A genome wide association study identified the classical type II cadherin CDH8 and CDH11, the protocadherin PCDH9, and the atypical cadherin FAT1 as candidate risk genes. This suggests that cadherin signaling pathways could be disrupted and may display increased vulnerability in autism.
Objectives:
We first determined the expression of autism risk cadherins CDH8, CDH11, PCDH9 and FAT1 in iPSC-derived cortical neurons from control and autism individuals to evaluate whether cadherin levels are commonly altered in autism. We then investigated the expression patterns of cadherins in developing mouse brains and in primary neurons at the subcellular level. Functional effects of cadherins on dendrite arborization were further examined. This study provides novel insights into common and distinct functions of different cadherins in neural circuit formation and the implication in autism.
Methods:
Western blot analyses were performed to evaluate the protein expression of CDH8, CDH11, PCDH9 and FAT1 in iPSC-derived cortical neurons, the developing mouse tissues from different brain areas as well as primary neurons. Subcellular localization as well as enrichment of cadherins in synaptic plasma membrane and postsynaptic densities were further analyzed using a synaptic fractionation assay and immunocytochemical labeling with neuronal marker MAP2 or synaptic markers PSD95, Synapsin 1 and GAT1. Sholl analysis was performed to measure the effect of cadherin knockdown on the complexity of dendritic arbors.
Results:
We found altered cadherin expression levels in iPSC-derived cortical neurons with an increase of CDH8 and a decrease of CDH11. Similar findings were observed in brains of CDH11 knockout mice. Temporal expression analysis in the developing mouse brains revealed increased expression of all cadherins examined at P7 and P14. Analysis of specific brain areas showed that CDH8, CDH11 and PCDH9 were prominently expressed in the cortex, hippocampus and thalamus/striatum whereas FAT1 expression was restricted to the cerebellum. CDH8, CDH11 and FAT1 localized to MAP2-positive dendrites and were enriched in synaptic plasma membrane and post-synaptic density. Moreover, CDH8 and CDH11 were associated with excitatory and inhibitory synaptic markers. Sholl analysis of hippocampal neurons revealed opposing effects on dendrite arborization after loss of CDH8 and CDH11 compared to PCDH9.
Conclusions:
The present study suggests altered expression profiles of cadherins in autism brains, thus strengthening the hypothesis of a central role of cadherins in autism. The findings presented here highlight that cadherins of different subfamilies are expressed in a developmental time window and in vulnerable brain areas implicated in autism. Taken together, by focusing on cadherins across different subfamilies, this study elucidates the role of different cadherin classes in the neurodevelopment of autism, both in animal models and in individuals with the condition.