Biology subjects

Alvizi, L.

Publications and source records attributed to Alvizi, L..

4 recordsLinked to original sources

bioRxiv2026

Reciprocal mechanochemical feedback couples neural crest migration and neurulation

Cephalic neurulation and neural crest migration are defining morphogenetic events of vertebrate head development. Although traditionally viewed as independent tissue-autonomous programs, their striking spatiotemporal overlap suggests functional coupling. Here, we show that these processes are linked by reciprocal mechanochemical feedback. We find that collective neural crest migration is essential for neural tube closure. As neural crest cells delaminate and invade the surrounding mesoderm, they remodel fibronectin at the neural crest-neural plate interface, creating a specialized extracellular matrix that both separates the two tissues and promotes neural tube morphogenesis by enabling radial intercalation and apical constriction of neural plate cells. This extracellular matrix remodeling requires neural crest-specific expression of the membrane-bound metalloproteinase MMP14. Conversely, neural tube morphogenesis drives neural crest migration. Mechanical compression generated during neural plate bending induces MMP14 expression in neural crest cells, triggering extracellular matrix remodeling that feeds back to facilitate neural tube closure. Together, our findings reveal that neurulation and neural crest migration are not independent morphogenetic programs but components of a self-reinforcing mechanochemical circuit that coordinates vertebrate head morphogenesis.

developmental biology↗

bioRxiv2025

Maternal-fetal inflammation affects Cdh1/E-cadherin epigenetic regulation and craniofacial development

Cleft lip with or without palate (CLP) is a multifactorial trait associated with environmental exposures such as smoking, alcohol consumption, and pro-inflammatory conditions during early pregnancy, as well as with both common and rare genetic variants. Our group identified CDH1 loss-of-function variants segregating in families with CLP, with incomplete penetrance linked to promoter hypermethylation. Previously, we demonstrated that gene-environment interactions driven by pro-inflammatory factors can induce this methylation, downregulate E-cadherin expression, and impair neural crest migration, thereby contributing to the etiology of CLP. However, the embryonic consequences of the two-hit CLP model (CDH1 haploinsufficiency combined with pro-inflammatory insult) have not yet been explored in mammals. Here, under single dose of floxed-Cdh1, we investigated the pro-inflammatory response at the maternal-fetal interface, its impact on cytokine and Cdh1 expression along the anteroposterior axis, the associated epigenetic landscape in the embryonic head, and the effect on cranial structures. We found that pro-inflammatory activation differentially signals to the embryo between anterior and posterior regions, impairing Cdh1/E-cadherin expression in NC cells of the head, accompanied by Cdh1 promoter hypermethylation and other differentially methylated genes involved in cell-junction maintenance. Our findings support a model in which maternal pro-inflammatory responses act as environmental factors that repress NC CDH1 expression through epigenetic mechanisms, contributing to CLP development by downregulating E-cadherin and potentially compromising overall epithelial integrity. Animal Ethics Committee (CEUA IB/USP) number approval: 394/2022

developmental biology↗

bioRxiv2019

"mir152 hypomethylation, potentially triggered by embryonic hypoxia, as a mechanism for non-syndromic cleft lip/palate"

Non-syndromic cleft lip/palate (NSCLP), the most common human craniofacial malformations, is a complex disorder given its genetic heterogeneity and multifactorial component revealed by genetic, epidemiological and epigenetic findings. Association of epigenetic variations with NSCLP has been made, however still of little functional investigation. Here we combined a reanalysis of NSCLP methylome data with genetic analysis and used both in vitro and in vivo approaches to dissect the functional effects of epigenetic changes. We found a frequent differentially methylated region in mir152, hypomethylated in NSCLP cohorts (21-26%), leading to mir152 overexpression. In vivo analysis using zebrafish embryos revealed that mir152 upregulation leads to craniofacial impairment analogue to palatal defects. Also, we demonstrated that zebrafish embryonic hypoxia leads to mir152 upregulation combined with mir152 hypomethylation and also analogue palatal alterations. We therefore suggest mir152 hypomethylation, potentially induced by hypoxia in early development, as a novel and frequent predisposing factor to NSCLP.

developmental biology↗

bioRxiv2018

DNA methylation mediates genetic liability to non-syndromic cleft lip/palate

BackgroundNon-syndromic cleft lip/palate (nsCL/P) is a complex trait with genetic and environmental risk factors. Around 40 distinct genetic risk loci have been identified for nsCL/P, but many reside in non-protein-coding regions with an unclear function. We hypothesised that one possibility is that the genetic risk variants influence susceptibility to nsCL/P through gene regulation pathways, such as those involving DNA methylation.\n\nMethodsUsing nsCL/P Genome-wide association study summary data and methylation data from four studies, we used Mendelian randomization and joint likelihood mapping to identify putative loci where genetic liability to nsCL/P may be mediated by variation in DNA methylation in blood.\n\nResultsThere was evidence at three independent loci, VAX1 (10q25.3), LOC146880 (17q23.3) and NTN1 (17p13.1), that liability to nsCL/P and variation in DNA methylation might be driven by the same genetic variant. Follow up analyses using DNA methylation data, derived from lip and palate tissue, and gene expression catalogues provided further insight into possible biological mechanisms.\n\nConclusionsGenetic variation may increase liability to nsCL/P by influencing DNA methylation and gene expression at VAX1, LOC146880 and NTN1.

genetics↗