Research Themes & Directions

Proper tissue function depends on the accurate design of tissue architecture and its preservation throughout organismal life. In the nervous system, one of the most remarkably complex tissues, efficient circuit function depends on the accurate patterning of neural circuit architecture during development, and the robust maintenance of circuit integrity during age progression. We investigate the mechanisms underlying these phenomena in vivo.

During an embryo’s life, cells with diverse fates and morphologies interact to give rise to well-defined neural circuit architecture. The early circuit assembly is fundamental for animal life and behavior; yet dissecting the cellular and molecular events initiating this assembly is a tantalising challenge. How do nervous system cells interact spatio-temporally while concurrently diversifying their fates? Which are the first cells that provide circuit scaffolds, and how do they pioneer assembly? How do circuit components grow and interact to establish specialised morphologies to achieve their functional connectivity in vivo?

After circuit development and throughout age progression, the intricate nervous system architecture must be maintained against environmental challenges, cellular and organismal aging changes. How do astroglial cells and neuron safeguard their intricate architecture and connectivity to guarantee faithful brain circuit function & animal behavior? What molecular mechanisms and cellular interactions ensure the fidelity with which the mature nervous system structure is maintained?

Centralized neural circuits consist mainly of neurons and glia – lineage related cell types in equal numbers. Neurons transmit electrical currents, while glia were long-thought to support passively neuron nutrition. However, glial cells are implicated in neural circuit development and function, in physiology and pathology. Which glial cell mechanisms and neuron-glial interactions define neural circuit architecture in vivo? Based on molecular and mechanistic homologies, neuronal and glial cells display properties conserved across distant species. Which overarching principles pattern circuit architecture across species?

Research Directions

-        Brain Pioneer Neuron Formation

Neural circuit assembly is thought to initiate by pioneer cells but the molecular identity, developmental mechanisms, cell interactions and molecular functions of brain pioneers often remain elusive. We recently identified pioneer neurons of specific identities initiating formation of the C. elegans brain circuit (Rapti et al, 2017). We now characterize the development and functional molecular repertoire of pioneer neurons in vivo (Sabou, Pal, Bhushan, Kumar, unpublished)

-        Brain Astroglial Cell Development

We demonstrated that C. elegans astroglial cells initiate brain circuit assembly by guiding pioneer neurons and follower components in the brain primordium, using conserved guidance cues (Rapti et al, 2017). Our studies and others demonstrate that these glial cells are counterparts of vertebrate embryonic radial glial cells and postembryonic astrocytes (Singhvi, Shaham, Rapti, 2024;  Rapti, 2024). We investigate in vivo mechanisms of development and interactions of C. elegans astroglial cells (Coraggio et al, 2024; Coraggio, Cibulskaite, Rapti, unpublished)

-        Glia–Neuron Crosstalk & Signaling in Circuit Assembly

We dissect mechanisms of brain assembly in vivo. We demonstrated that brain assembly in C. elegans is established through glia-neuron interactions, cellular and molecular hierarchies (Rapti et al, 2017). Specific pioneer neurons and glial cells interact and cooperate to guide follower circuit components, through signaling of conserved molecular cues. We uncover that the hierarchical, glia-mediated circuit assembly is underlined by extensive molecular synergies. We reveal new synergistic factors and dissect their signaling roles in circuit assembly in vivo, using modifier genetic screens. We implicate guidance and adhesion molecules, trafficking factors & enzymes, morphogen pathways, extracellular matrix (ECM) and neighboring cells, in the glia-neuron signaling brain assembly (Rapti et al, 2017 ; Caroti, Mungo, Gandara, Rapti, in prep; Marschlich, Georgakopoulos, Rapti, unpublished).

-        Maintenance of Glia & Neuron Integrity

Beyond initial circuit assembly, molecular & cellular interactions regulate the integrity of circuit architecture in age progression in vivo. We identified mechanisms devoted to safeguarding the intricate architecture of glial cells and neurons, towards functional neural connectivity, circuit and animal healthspan. We demonstrated that glial cells interact with ECM, epithelial proteostasis, biomechanics, and the environment to integrate responses to temperature and mechanical stress towards circuit stability (Coraggio et al, 2024). We also implicated ECM remodeling mechanisms in circuit architecture (Nadour et al, biorxiv). We study mechanisms that regulate neural cell architecture during age progression and through crosstalk with biomechanics.

-        Dissecting Conserved Principles Across Species

We describe remarkable similarities between the C. elegans brain neuropil and vertebrate circuits like the neural tube (Rapti et al, 2017; Singhvi, Shaham, Rapti, 2024;  Rapti, 2024). Genes that we implicated in brain architecture have homologs associated with human neurodevelopmental & neurodegenerative disorders, including autism, epilepsies, and Alzheimer’s disease. We establish collaborations to address conserved mechanisms of circuit assembly across species.