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Dynamic scaffolds for neuronal signaling: in silico analysis of the TANC protein family.

ABSTRACT: The emergence of genes implicated across multiple comorbid neurologic disorders allows to identify shared underlying molecular pathways. Recently, investigation of patients with diverse neurologic disorders found TANC1 and TANC2 as possible candidate disease genes. While the TANC proteins have been reported as postsynaptic scaffolds influencing synaptic spines and excitatory synapse strength, their molecular functions remain unknown. Here, we conducted a comprehensive in silico analysis of the TANC protein family to characterize their molecular role and understand possible neurobiological consequences of their disruption. The known Ankyrin and tetratricopeptide repeat (TPR) domains have been modeled. The newly predicted N-terminal ATPase domain may function as a regulated molecular switch for downstream signaling. Several putative conserved protein binding motifs allowed to extend the TANC interaction network. Interestingly, we highlighted connections with different signaling pathways converging to modulate neuronal activity. Beyond a known role for TANC family members in the glutamate receptor pathway, they seem linked to planar cell polarity signaling, Hippo pathway, and cilium assembly. This suggests an important role in neuron projection, extension and differentiation.

SUBMITTER: Gasparini A

PROVIDER: S-EPMC5533708 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Dynamic scaffolds for neuronal signaling: in silico analysis of the TANC protein family.

Gasparini Alessandra A Tosatto Silvio C E SCE Murgia Alessandra A Leonardi Emanuela E

Scientific reports 20170728 1

The emergence of genes implicated across multiple comorbid neurologic disorders allows to identify shared underlying molecular pathways. Recently, investigation of patients with diverse neurologic disorders found TANC1 and TANC2 as possible candidate disease genes. While the TANC proteins have been reported as postsynaptic scaffolds influencing synaptic spines and excitatory synapse strength, their molecular functions remain unknown. Here, we conducted a comprehensive in silico analysis of the T ...[more]

PMID: 28754924

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Project description:BackgroundHematopoietic stem and progenitor cell (HSPC) subsets in mice have previously been studied using cell surface markers, and more recently single-cell technologies. The recent revolution of single-cell analysis is substantially transforming our understanding of hematopoiesis, confirming the substantial heterogeneity of cells composing the hematopoietic system. While dynamic molecular changes at the DNA/RNA level underlying hematopoiesis have been extensively explored, a broad understanding of single-cell heterogeneity in hematopoietic signaling programs and landscapes, studied at protein level and reflecting post-transcriptional processing, is still lacking. Here, we accurately quantified the intracellular levels of 9 phosphorylated and 2 functional proteins at the single-cell level to systemically capture the activation dynamics of 8 signaling pathways, including EGFR, Jak/Stat, NF-κB, MAPK/ERK1/2, MAPK/p38, PI3K/Akt, Wnt, and mTOR pathways, during mouse hematopoiesis using mass cytometry.ResultsWith fine-grained analyses of 3.2 million of single hematopoietic stem and progenitor cells (HSPCs), and lineage cells in conjunction with multiparameter cellular phenotyping, we mapped trajectories of signaling programs during HSC differentiation and identified specific signaling biosignatures of cycling HSPC and multiple differentiation routes from stem cells to progenitor and lineage cells. We also investigated the recovery pattern of hematopoietic cell populations, as well as signaling regulation in these populations, during hematopoietic reconstruction. Overall, we found substantial heterogeneity of pathway activation within HSPC subsets, characterized by diverse patterns of signaling.ConclusionsThese comprehensive single-cell data provide a powerful insight into the intracellular signaling-regulated hematopoiesis and lay a solid foundation to dissect the nature of HSC fate decision. Future integration of transcriptomics and proteomics data, as well as functional validation, will be required to verify the heterogeneity in HSPC subsets during HSC differentiation and to identify robust markers to phenotype those HSPC subsets.

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Dataset Information

Dynamic scaffolds for neuronal signaling: in silico analysis of the TANC protein family.

Publications

Dynamic scaffolds for neuronal signaling: in silico analysis of the TANC protein family.

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