Biology subjects

Odent, S.

Publications and source records attributed to Odent, S..

3 recordsLinked to original sources

bioRxiv2025

Mapping the temporal and functional landscape of Sonic Hedgehog signaling reveals new insights into early human forebrain development

The early patterning of the anterior neuroectoderm constitutes a fundamental blueprint for human brain development, orchestrated by multiple signaling pathways. Among them, Sonic Hedgehog (SHH) plays a key influence. However, the transcriptional programs it engages remain poorly defined due to the limited accessibility of human brain tissue. To address this, we established a human induced pluripotent stem cells-derived model of early forebrain differentiation, enabling a precise dissection of SHH-driven transcriptional programs over time. RNA sequencing revealed dynamic transcriptomic landscapes governing forebrain neuroectoderm specification and dorsoventral patterning. In addition, pharmacological perturbation of SHH signaling allowed to identify an extended collection of novel forebrain regionalization markers, including several previously unrecognized dorsal and ventral determinants. By combining in vivo human datasets with functional mouse studies, we enhanced the biological relevance of this extended network of putative SHH-regulated genes and long non-coding RNAs in shaping early forebrain architecture. This work advances our understanding of the temporal dynamics of SHH signaling in human neurodevelopment and provide critical molecular insights into midline brain malformations. It offers a promising foundation for advancing molecular diagnosis of complex rare genetic disorders. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/654466v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@dac307org.highwire.dtl.DTLVardef@3a051borg.highwire.dtl.DTLVardef@12559c9org.highwire.dtl.DTLVardef@129cbec_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2022

Gene editing is suitable to treat GM1 Gangliosidosis: a proof-of-concept study

Ganglioside-monosialic acid (GM1) gangliosidosis, a rare autosomal recessive disorder, is frequently caused by deleterious single nucleotide variants (SNVs) in GLB1 gene. These variants result in reduced {beta}-galactosidase ({beta}-gal) activity, leading to neurodegeneration associated with premature death. Currently, no effective therapy for GM1 gangliosidosis is available. Three ongoing clinical trials aim to deliver a functional copy of the GLB1 gene to stop disease progression. Here, we show that 41% of GLB1 pathogenic SNVs might be cured by adenine base editors (ABEs). Our results demonstrate that ABE efficiently corrects the pathogenic allele in patient-derived fibroblasts, restoring a therapeutic level of {beta}-gal activity. Unbiased off-target DNA analysis did not detect off-target editing activity in treated patients cells except a bystander edit without consequences on {beta}-gal activity. Altogether our results suggest that gene editing is an alternative strategy to cure GM1 gangliosidosis, by correcting the root cause of disease and avoiding repetitive adeno-associated virus injections.

genetics↗

bioRxiv2018

Integrated Clinical and Omics Approach to Rare Diseases: Novel Genes and Oligogenic Inheritance in Holoprosencephaly

PurposeHoloprosencephaly (HPE) is a pathology of forebrain development characterized by high phenotypic and locus heterogeneity. Seventeen genes are known so far in HPE but the understanding of its genetic architecture remains to be refined. Here, we investigated the oligogenic nature of HPE resulting from accumulation of variants in different relevant genes.\n\nMethodsExome data from 29 patients diagnosed with HPE and 51 relatives from 26 unrelated families were analyzed. Standard variant classification approach was improved with a gene prioritization strategy based on clinical ontologies and gene co-expression networks. Clinical phenotyping and exploration of cross-species similarities were further performed on a family-by-family basis.\n\nResultsWe identified 232 rare deleterious variants in HPE patients representing 180 genes significantly associated with key pathways of forebrain development including Sonic Hedgehog (SHH) and Primary Cilia. Oligogenic events were observed in 10 families and involved novel HPE genes including recurrently mutated genes (FAT1, NDST1, COL2A1 and SCUBE2) and genes implicated in cilia function.\n\nConclusionsThis study reports novel HPE-relevant genes and reveals the existence of oligogenic cases resulting from several mutations in SHH-related genes. It also underlines that integrating clinical phenotyping in genetic studies will improve the identification of causal variants in rare disorders.

genetics↗