Uncovering the genetic blueprint of theC. elegansnervous system

Abstract

Despite rapid advances in connectome mapping and neuronal genetics, we lack theoretical and computational tools to unveil, in an experimentally testable fashion, the genetic mechanisms that govern neuronal wiring. Here we introduce a computational framework to link the adjacency matrix of a connectome to the expression patterns of its neurons, helping us uncover a set of genetic rules that govern the interactions between neurons in contact. The method incorporates the biological realities of the system, accounting for noise from data collection limitations, as well as spatial restrictions. The resulting methodology allows us to infer a network of 19 innexin interactions that govern the formation of gap junctions in Caenorhabditis elegans, five of which are already supported by experimental data. As advances in single-cell gene expression profiling increase the accuracy and the coverage of the data, the developed framework will allow researchers to systematically infer experimentally testable connection rules, offering mechanistic predictions for synapse and gap junction formation.

Neural Tissue Homeostasis and Repair Is Regulated via CS and DS Proteoglycan Motifs

“…Studies on the fruit fly, D. melanogaster ( FitzGerald et al, 2006 ; Nishihara, 2010 ; Losada-Perez et al, 2016 ; Davis et al, 2019 ) and the nematode C. elegans ( White et al, 1976 ; Mulcahy et al, 2018 ; Schafer, 2018 ; Kovács et al, 2020 ; White, 2020 ) have provided insightful information on the role of the ECM and some of its specific components in neural development and tissue morphogenesis in a whole organism environment. White et al (1986) undertook the first complete mapping study of the nematode’s nervous system using manual reconstruction of serial electron micrographs, to characterize the morphology of each of the 302 neurons in the adult nematode and their interconnected chemical and electrical synapses.…”

“…Studies on the fruit fly, D. melanogaster (FitzGerald et al, 2006;Nishihara, 2010;Losada-Perez et al, 2016;Davis et al, 2019) and the nematode C. elegans (White et al, 1976;Mulcahy et al, 2018;Schafer, 2018;Kovács et al, 2020;White, 2020) have provided insightful information on the role of the ECM and some FIGURE 2 | The biosynthesis of CS and DS chains showing their diverse disaccharide glycoforms that are functional in the juvenile and adult CNS/PNS and during the development and repair of the CNS/PNS. Biosynthesis of the tetrasaccharide linker sequence by addition of a xylose residue to a serine residue in the proteoglycan core protein followed by addition of two Galactose and a GlcA residue (a).…”

A Transcriptome Community-and-Module Approach of the Human Mesoconnectome

“…By choosing communities instead of cliques and rich clubs, we obtained the highest number of mesostructures in the network hierarchy organization while ensuring lesser topological constraints [33,72]. A clique analysis would only retain minuscule fully connected gene subgraphs, restricting the identification of specialized brain pathways [31,32]. In contrast, a rich-club analysis would yield essential genes that modulate the GRN [73,74] without considering the complexity of transcriptional mechanisms to carry out the basal molecular pathways within the brain.…”

“…An approach to exploring those brain compartments is through graph analysis, particularly through the graph mesostructures, such as cliques, communities, and modules. Barabási and Barabási and Kovács et al studied brain genetics through cliques; however, this work was unable to establish brain-wide connectivity [31,32], while Betzel et al conducted a comparative analysis of the fMRI voxel communities of various connectomes but was only able to correlate with coexpression networks in the mouse [33].…”

Complex Computation from Developmental Priors

“…1:The Genetic neuroEvolution Model. (a) Visualization of the Genetic Connectome Model[14,15]. Matrices X i and X o represent the gene expression of input and output neurons, respectively.…”