Homophilic Protocadherin Cell-Cell Interactions Promote Dendrite Complexity

Abstract

SUMMARY Growth of a properly complex dendrite arbor is a key step in neuronal differentiation and a prerequisite for neural circuit formation. Diverse cell surface molecules, such as the clustered protocadherins (Pcdhs), have long been proposed to regulate circuit formation through specific cell-cell interactions. Here, using transgenic and conditional knockout mice to manipulate γ-Pcdh repertoire in the cerebral cortex, we show that the complexity of a neuron’s dendritic arbor is determined by homophilic interactions with other cells. Neurons expressing only one of the 22 γ-Pcdhs can exhibit either exuberant, or minimal, dendrite complexity depending only on whether surrounding cells express the same isoform. Furthermore, loss of astrocytic γ-Pcdhs, or disruption of astrocyte-neuron homophilic matching, reduces dendrite complexity cell non-autonomously. Our data indicate that γ-Pcdhs act locally to promote dendrite arborization via homophilic matching and confirm that connectivity in vivo depends on molecular interactions between neurons, and between neurons and astrocytes.

Regional astrocyte IFN signaling restricts pathogenesis during neurotropic viral infection

“…shown in numerous studies to have reliably astrocyte-specific expression (22)(23)(24)(25). Consistent with this, we observed deletion of Ifnar on cortical and cerebellar astrocytes, with intact expression of the receptor on nonastrocytic cells.…”

“…Given the findings from our own studies demonstrating that IFNAR signaling in astrocytes enhances in vitro BBB integrity in response to WNV (4), we used Ifnar fl/fl Gfap-Cre mice, in which IFNAR signaling was abrogated in glial fibrillary acidic protein-expressing (GFAP-expressing) astrocytes, to evaluate the contribution of astrocyte IFNAR signaling to WNV pathogenesis and disease. For these studies, we chose the Gfap-Cre line 77.6, which was previously shown to exhibit a Cre expression that is more specific to astrocytes than to other GfapCre lines (22)(23)(24)(25). We also used an established in vitro BBB model to examine how forebrain versus hindbrain astrocytes differentially regulate barrier function.…”

Regulation of neural circuit formation by protocadherins

“…Consistent with this, sequence analysis across α-Pcdh and γ-Pcdh family members reveals more divergence in EC2/3 than in other EC domains [50,51]. While homophilic interaction of γ-Pcdhs can induce stable adhesive cell-cell contacts and cell aggregation [50,51,53,54], some phenotypes (see below) in Pcdhg and Pcdha mutant mice are consistent with the possibility that homophilic interaction leads to repulsive signaling [55-58]. …”

“…Recently, Molumby et al [54] presented evidence that, at least in the cerebral cortex, homophilic γ-Pcdh trans- interactions between neurons, and between neurons and astrocytes, can positively promote dendrite growth and arbor complexity. Using the same Cre-inducible, single-isoform transgenic mouse lines reported by Lefebvre et al [56], Molumby et al [54] generated mice in which labeled cortical pyramidal neurons encountered increased or decreased γ-Pcdh homophilic matching with surrounding cells in vivo.…”

“…Using the same Cre-inducible, single-isoform transgenic mouse lines reported by Lefebvre et al [56], Molumby et al [54] generated mice in which labeled cortical pyramidal neurons encountered increased or decreased γ-Pcdh homophilic matching with surrounding cells in vivo. Neurons surrounded entirely by other neurons and astrocytes expressing the same single γ-Pcdh isoform exhibited significantly increased dendrite growth and complexity; in contrast, isolated neurons expressing a single isoform that few surrounding cells expressed exhibited severely deficient dendrite arbor complexity.…”