Biology subjects

Walvekar, A.

Publications and source records attributed to Walvekar, A..

7 recordsLinked to original sources

bioRxiv2025

Junctional Heterogeneity Shapes Epithelial Morphospace

Tissues and organs develop a wide range of shapes, sizes and cellular organisations, linked to their physiological function. How developmental programmes generate this organisational diversity remains poorly understood. Inner ear sensory epithelia in birds, fish, and mammals provide a tractable system to address this question, as their constituent cells arise from a common developmental lineage, share molecular signatures, and have conserved physiological functions, yet assemble into distinct cellular organisations. These epithelia contain two principal cell types, mechanosensory hair cells (HCs) and supporting cells (SCs), organised into mosaics. Here, we developed a three-parameter morphospace that quantitatively captures epithelial organisation, enabling comparisons across species, structures and developmental stages. Combining this framework with genetic perturbation, biochemical analysis and live imaging reveals that the diverse mature organisations emerge from a common early organisational state constrained by Notch-Delta signalling. During subsequent development, the differential localisation of adhesion molecules (Cdh1,2 and Nectin) and contractility-associated proteins (NM2 and -actinin-4) at HC-SC and SC-SC junctions establishes junctional asymmetries. Across species, asymmetry drives stable circular HCs and actively remodelling SCs. The coexistence of these cell shape states drives selective intercalation, guiding each epithelium along a distinct trajectory through morphospace toward its mature organisation. These findings identify cell-shape dynamics as a developmental mechanism for generating organisational diversity in sensory, and potentially other, epithelia.

developmental biology↗

bioRxiv2023

MORPHOGENIC VERSUS MITOGENIC ROLES OF SHH ARE SEGREGATED ON DISTINCT EXOSOMES REGULATED BY CELLULAR RAB7 LEVELS

The secreted signaling molecule, Sonic hedgehog (Shh) is involved in patterning and growth of various embryonic tissues across species. This lipid-anchored protein is secreted on extracellular vesicles to activate signaling. Shh has two functions during spinal cord development, acting as a morphogen to pattern the ventral neural tube and a mitogen to maintain neural progenitors. Here, we find that these activities are segregated on to two distinct pools of exosomes. Shh secreted on a classical exosomal pool (Shh-P150) is able to activate ventral threshold targets in the neural tube. In contrast, the mitogenic activity, is elicited by a lighter exosomal pool (Shh-P450). We further show that cellular environment plays a major role in regulating the biogenesis of P150 versus P450 by modulating Rab7 levels. We find that active Rab7 is necessary for ventral neural tube patterning through the regulation of Shh-P150 secretion. The cellular mechanisms involved in packaging and secretion of Shh with different partners on P150 or P450 pools may be more general, enabling the separation of functional activities of signaling molecules during development and disease.

developmental biology↗

bioRxiv2022

Methionine uptake via SLC43A2 transporter is essential for regulatory T lymphocyte survival

It is increasingly clear that cell death, survival or growth decisions of T lymphocyte subsets depend on interplay between cytokine-dependent and metabolic processes. What the metabolic requirements of T regulatory cells (Tregs) for their survival are, and how these requirements are satisfied remain to be fully understood. In this study, we identified a necessary requirement of methionine uptake and utilization for Tregs survival upon interleukin 2 (IL-2) deprivation. Activated Tregs have high methionine uptake and consumption to S-adenosyl methionine (SAM) and S-adenosyl homocysteine (SAH). This methionine uptake is essential for Tregs survival, and is regulated by Notch1 activity. Notch1 controls the expression of the solute carrier protein SLC43A2 transporter during IL-2 deprivation. SLC43A2 is necessary for sufficient methionine uptake, and determines Tregs viability upon IL-2 withdrawal. Collectively, we identify a specifically regulated mechanism of methionine import in Tregs that is necessary for the survival of these cells. This highlights the need for methionine availability and metabolism in contextually regulating cell death in an immunosuppressive population of T lymphocytes.

immunology↗

bioRxiv2020

Metabolite plasticity drives carbon-nitrogen resource budgeting to enable division of labor in a clonal community

Previously, we discovered that in glucose-limited yeast colonies, metabolic constraints drive cells into groups exhibiting gluconeogenic and glycolytic metabolic states. Here, threshold amounts of trehalose - a limiting, produced resource, controls the emergence and self-organization of the cells exhibiting the glycolytic state, by acting as a carbon source to fuel these metabolic demands (Varahan et al., 2019). We now discover that the plasticity of use of a non-limiting resource, aspartate, controls both resource production and the emergence of heterogeneous cell states, based on differential cellular metabolic budgeting. In gluconeogenic cells, aspartate provides carbon for trehalose production, while in glycolytic cells using trehalose for carbon, aspartate supplies nitrogen to drive nucleotide synthesis. This metabolic plasticity of aspartate enables carbon-nitrogen budgeting, thereby driving the biochemical self-organization of distinct cell states. Through this organization, cells in each state exhibit true division of labor, providing bet-hedging and growth/survival advantages for the whole community.

cell biology↗

bioRxiv2019

Metabolic constraints drive self-organization of specialized cell groups

How phenotypically distinct states in isogenic cell populations appear and stably co-exist remains an unresolved question. We find that within a clonal yeast colony developing in low glucose, cells arrange into metabolically disparate cell groups. Using this system, we model and experimentally identify metabolic constraints sufficient to drive such assembly. Beginning in a gluconeogenic state, cells in a contrary state, exhibiting high pentose phosphate pathway activity, spontaneously appear and proliferate, in a spatially constrained manner. The gluconeogenic cells in the developing colony produce a resource, which we identify as trehalose. At threshold concentrations of trehalose, cells in the new metabolic state emerge and proliferate. A self-organized system establishes, where cells in this new state are sustained by trehalose consumption, which thereby restrains other cells in the trehalose producing, gluconeogenic state. Our work suggests simple physico-chemical principles that determine how isogenic cells spontaneously self-organize into structured assemblies in complimentary, specialized states.

cell biology↗

bioRxiv2018

A tRNA modification balances carbon and nitrogen metabolism by regulating phosphate homeostasis, to couple metabolism to cell cycle progression.

Cells must appropriately sense and integrate multiple metabolic resources to commit to proliferation. Here, we report that cells regulate carbon and nitrogen metabolic homeostasis through tRNA U34-thiolation. Despite amino acid sufficiency, tRNA-thiolation deficient cells appear amino acid starved. In these cells, carbon flux towards nucleotide synthesis decreases, and trehalose synthesis increases, resulting in a starvation-like metabolic signature. Thiolation mutants have only minor translation defects. However, these cells exhibit strongly decreased expression of phosphate homeostasis genes, resulting in an effectively phosphate-limited state. Reduced phosphate enforces a metabolic switch, where glucose-6-phosphate is routed towards storage carbohydrates. Notably, trehalose synthesis, which releases phosphate and thereby restores phosphate availability, is central to this metabolic rewiring. Thus, cells use thiolated tRNAs to perceive amino acid sufficiency, and balance carbon and amino acid metabolic flux to maintain metabolic homeostasis, by controlling phosphate availability. These results further biochemically explain how phosphate availability determines a switch to a starvation-state.

biochemistry↗

bioRxiv2018

Methionine coordinates a hierarchically organized anabolic program through GCN4

Methionine availability during overall amino acid limitation metabolically reprograms cells to support proliferation, the underlying basis for which remains unclear. Here, we construct the organization of this methionine mediated anabolic program, using yeast. Combining comparative transcriptome analysis, biochemical and metabolic flux based approaches, we discover that methionine rewires overall metabolic outputs by increasing the activity of three key regulatory nodes. These are: the pentose phosphate pathway coupled with reductive biosynthesis, and overall transamination capacity, including the synthesis of glutamate/glutamine. These provides the cofactors or substrates that enhance subsequent rate-limiting reactions in the synthesis of costly amino acids, and nucleotides, which are also induced in a methionine dependent manner. This thereby results in a biochemical cascade establishing an overall anabolic program. For this methionine mediated anabolic program leading to proliferation, cells co-opt a \"starvation stress response\" regulator, Gcn4p. Collectively, our data suggest a hierarchical metabolic framework explaining how methionine mediates an anabolic switch.

systems biology↗