@article {161134, title = {The patterning and proliferation roles of Shh are partitioned on distinct exosomes.}, journal = {Dev Biol}, volume = {528}, year = {2025}, month = {2025 Dec}, pages = {239-254}, abstract = {

Sonic hedgehog (Shh) is a pivotal morphogen in spinal cord development, orchestrating both ventral neural patterning and progenitor proliferation. How these distinct outcomes are specified has remained elusive. Here, we uncover that Shh is secreted via two biochemically and functionally distinct exosomal pools. A dense vesicle fraction, Shh-P150, drives Smoothened-Gli1 signalling to establish ventral progenitor identities, while a lighter pool, Shh-P450, activates a Smoothened-Gαi-dependent pathway that enhances progenitor proliferation without inducing ventral fate. We identify Rab7, a late endosomal regulator, as essential for Shh-P150 biogenesis and for notochord-mediated ventral neural patterning. Loss of Rab7 biases secretion toward the proliferative Shh-P450 pool and disrupts morphogenetic signalling. These findings establish exosomal packaging as a molecular switch that toggles Shh between its mitogenic and morphogenetic roles. By linking exosome biogenesis to developmental outcomes, our work reveals a novel mechanism that safeguards the balance between pattern formation and progenitor expansion during neural tube development, with implications for both developmental disorders and disease contexts where Shh signalling is misregulated.

}, keywords = {Animals, Body Patterning, Cell Proliferation, Exosomes, Gene Expression Regulation, Developmental, Hedgehog Proteins, Mice, Neural Tube, Notochord, rab GTP-Binding Proteins, rab7 GTP-Binding Proteins, Signal Transduction, Smoothened Receptor, Spinal Cord, Zinc Finger Protein GLI1}, issn = {1095-564X}, doi = {10.1016/j.ydbio.2025.09.017}, author = {Walvekar, Ankita and Pandey, Shivangi and Kamat, Siddhesh S and Ladher, Raj K and Vyas, Neha} } @article {121149, title = {Molecular markers for early stratification of disease severity and progression in COVID-19.}, journal = {Biol Methods Protoc}, volume = {7}, year = {2022}, month = {2022}, pages = {bpac028}, abstract = {

COVID-19 infections have imposed immense pressure on the healthcare system of most countries. While the initial studies have identified better therapeutic and diagnostic approaches, the disease severity is still assessed by close monitoring of symptoms by healthcare professionals due to the lack of biomarkers for disease stratification. In this study, we have probed the immune and molecular profiles of COVID-19 patients at 48-h intervals after hospitalization to identify early markers, if any, of disease progression and severity. Our study reveals that the molecular profiles of patients likely to enter the host-immune response-mediated moderate or severe disease progression are distinct even in the early phase of infection when severe symptoms are not yet apparent. Our data from 37 patients suggest that at hospitalization, interleukins (IL6) (\>300\ pg/ml) and IL8 levels (\>200\ pg/ml) identify cytokine-dependent disease progression. Monitoring their levels will facilitate timely intervention using available immunomodulators or precision medicines in those likely to progress due to cytokine storm and help improve outcomes. Additionally, it will also help identify cytokine-independent progressive patients, not likely to benefit from immunomodulators or precision drugs.

}, issn = {2396-8923}, doi = {10.1093/biomethods/bpac028}, author = {Kashyap, Anusha and Sebastian, Savitha Anne and Krishnaiyer NarayanaSwamy, Sree Raksha and Raksha, KalyanKumar and Krishnamurthy, Hanumanthappa and Krishna, Bhuvana and D{\textquoteright}Souza, George and Idiculla, Jyothi and Vyas, Neha} } @article {91136, title = {Exovesicular-Shh confers Imatinib resistance by upregulating Bcl2 expression in chronic myeloid leukemia with variant chromosomes.}, journal = {Cell Death Dis}, volume = {12}, year = {2021}, month = {2021 Mar 11}, pages = {259}, abstract = {

Chronic myeloid leukemia (CML) patients with complex chromosomal translocations as well as non-compliant CML patients often demonstrate short-lived responses and poor outcomes on the current therapeutic regimes using Imatinib and its variants. It has been derived so far that leukemic stem cells (LSCs) are responsible for Imatinib resistance and CML progression. Sonic hedgehog (Shh) signaling has been implicated in proliferation of this Imatinib-resistant CD34(+) LSCs. Our work here identifies the molecular mechanism of Shh-mediated mutation-independent Imatinib resistance that is most relevant for treating CML-variants and non-compliant patients. Our results elucidate that while Shh can impart stemness, it also upregulates expression of anti-apoptotic protein-Bcl2. It is the upregulation of Bcl2 that is involved in conferring Imatinib resistance to the CD34(+) LSCs. Sub-toxic doses of Bcl2 inhibitor or Shh inhibitor (

}, issn = {2041-4889}, doi = {10.1038/s41419-021-03542-w}, author = {Dalal, Hamza and Subramanian, Sitalakshmi and V P, Snijesh and Gowda, Divya A and H, Krishnamurthy and Damodar, Sharat and Vyas, Neha} } @article {77385, title = {The primary cilium dampens proliferative signaling and represses a G2/M transcriptional network in quiescent myoblasts.}, journal = {BMC Mol Cell Biol}, volume = {21}, year = {2020}, month = {2020 Apr 15}, pages = {25}, abstract = {

BACKGROUND: Reversible cell cycle arrest (quiescence/G0) is characteristic of adult stem cells and is actively controlled at multiple levels. Quiescent cells also extend a primary cilium, which functions as a signaling hub. Primary cilia have been shown to be important in multiple developmental processes, and are implicated in numerous developmental disorders. Although the association of the cilium with G0 is established, the role of the cilium in the control of the quiescence program is still poorly understood.

RESULTS: Primary cilia are dynamically regulated across different states of cell cycle exit in skeletal muscle myoblasts: quiescent myoblasts elaborate a primary cilium in vivo and in vitro, but terminally differentiated myofibers do not. Myoblasts where ciliogenesis is ablated using RNAi against a key ciliary assembly protein (IFT88) can exit the cell cycle but display an altered quiescence program and impaired self-renewal. Specifically, the G0 transcriptome in IFT88 knockdown cells is aberrantly enriched for G2/M regulators, suggesting a focused repression of this network by the cilium. Cilium-ablated cells also exhibit features of activation including enhanced activity of Wnt and mitogen signaling and elevated protein synthesis via inactivation of the translational repressor 4E-BP1.

CONCLUSIONS: Taken together, our results show that the primary cilium integrates and dampens proliferative signaling, represses translation and G2/M genes, and is integral to the establishment of the quiescence program.

}, issn = {2661-8850}, doi = {10.1186/s12860-020-00266-1}, author = {Venugopal, Nisha and Ghosh, Ananga and Gala, Hardik and Aloysius, Ajoy and Vyas, Neha and Dhawan, Jyotsna} } @article {29629, title = {Wnt and Hedgehog: Secretion of Lipid-Modified Morphogens.}, journal = {Trends Cell Biol}, volume = {28}, year = {2018}, month = {2018 Feb}, pages = {157-170}, abstract = {

Morphogens are signaling molecules produced by a localized source, specifying cell fate in a graded manner. The source secretes morphogens into the extracellular milieu to activate various target genes in an autocrine or paracrine manner. Here we describe various secreted forms of two canonical morphogens, the lipid-anchored Hedgehog (Hh) and Wnts, indicating the involvement of multiple carriers in the transport of these morphogens. These different extracellular secreted forms are likely to have distinct functions. Here we evaluate newly identified mechanisms that morphogens use to traverse the required distance to activate discrete paracrine signaling.

}, issn = {1879-3088}, doi = {10.1016/j.tcb.2017.10.003}, author = {Parchure, Anup and Vyas, Neha and Mayor, Satyajit} } @article {3536, title = {Oligomerization and endocytosis of Hedgehog is necessary for its efficient exovesicular secretion.}, journal = {Mol Biol Cell}, volume = {26}, year = {2015}, month = {2015 Dec 15}, pages = {4700-17}, abstract = {

Hedgehog (Hh) is a secreted morphogen involved in both short- and long-range signaling necessary for tissue patterning during development. It is unclear how this dually lipidated protein is transported over a long range in the aqueous milieu of interstitial spaces. We previously showed that the long-range signaling of Hh requires its oligomerization. Here we show that Hh is secreted in the form of exovesicles. These are derived by the endocytic delivery of cell surface Hh to multivesicular bodies (MVBs) via an endosomal sorting complex required for transport (ECSRT)-dependent process. Perturbations of ESCRT proteins have a selective effect on long-range Hh signaling in Drosophila wing imaginal discs. Of importance, oligomerization-defective Hh is inefficiently incorporated into exovesicles due to its poor endocytic delivery to MVBs. These results provide evidence that nanoscale organization of Hh regulates the secretion of Hh on ESCRT-derived exovesicles, which in turn act as a vehicle for long-range signaling.

}, issn = {1939-4586}, doi = {10.1091/mbc.E15-09-0671}, author = {Parchure, Anup and Vyas, Neha and Ferguson, Charles and Parton, Robert G and Mayor, Satyajit} }