Biology subjects

Soret, R.

Publications and source records attributed to Soret, R..

3 recordsLinked to original sources

bioRxiv2026

GDNF enemas improve epithelial and immune defects in both aganglionic and ganglionic colon of Hirschsprung mice

Hirschsprung disease (HSCR) is a severe birth defect where ganglia of the enteric nervous system (ENS) are missing from distal bowel. The aganglionic segment is also characterized by increased epithelial permeability and pro-inflammatory immune activation. These problems may sequentially lead to translocation of gut microbes into the colon wall and systemic circulation, resulting in enterocolitis and sepsis. Current HSCR treatment via surgical resection of the aganglionic segment is lifesaving but not curative, often leaving patients with persistent gastrointestinal complications including recurrent risk of enterocolitis. As alternative, we are developing a regenerative medicine strategy based on in situ stimulation of tissue-resident ENS progenitors via rectal administration of the neurotrophic factor GDNF. Here, we report that GDNF-based therapy has pleiotropic gastrointestinal effects in a mouse model of short-segment HSCR, beyond its role in ENS regeneration. Interestingly, we found that these protective effects are not restricted to the aganglionic distal colon, also positively impacting the ENS-containing proximal colon. GDNF treatment reduces bacterial translocation both locally and in peripheral organs, and this is associated with recovery of the key epithelial junction proteins CLDN3, ZO1 and DSG2. Furthermore, multiparameter flow cytometry-based analysis of 55 lymphoid and 17 myeloid cell subtypes revealed that GDNF treatment has global anti-inflammatory effects, preferentially affecting innate over adaptive immunity. Overall, these findings highlight a critical role for GDNF treatment in reestablishing proper epithelial and immune cell homeostasis, offering promising therapeutic avenues not only for HSCR but also potentially for other intestinal disorders with overlapping pathophysiology.

developmental biology↗

bioRxiv2026

Compromised striatal structure and function in mouse models of RARB-related disorder

Dominant variants in the retinoic acid receptor beta (RARB) gene cause a complex disorder known as RARB-related disorder (RARB-RD), characterized by multiple congenital anomalies, global developmental delay, and dystonia. RARB-RD variants have been classified as either gain-of-function (GOF) or dominant-negative (DN) based on their cell-based transcriptional responses to retinoids. To investigate the mechanisms underlying this disorder, we generated mouse models carrying either the p.R387C or p.L402P RARB-RD variant, previously categorized as GOF and DN, respectively. Homozygous mice for either RARB-RD variant died perinatally with colonic aganglionosis, while heterozygous mice survived and recapitulated several features of RARB-RD. In addition to microphthalmia, both RarbR387C/+and RarbL402P/+ mice exhibited progressive coordination deficits, increased active-phase locomotor activity, and cognitive impairment in the novel object recognition test. In contrast, mice heterozygous for a null allele of Rarb (Rarb+/-) did not display these abnormalities. In the brain, Rarb is predominantly expressed in the two major populations of projection neurons of the striatum recognizable by the expression of dopamine receptors D1R/Drd1 and D2R/Drd2. Marker analysis revealed a reduction in Drd2-expressing neurons without changes in Drd1-expressing neurons in both RARB-RD models. Furthermore, RARB-RD mice showed partial resistance to the cataleptic effects of haloperidol, a D2R-specific antagonist. These behavioral, cellular, and dopaminergic deficits--though not the cognitive impairments--have previously been observed in Rarb-/- mice. To determine whether the in vitro effects of RARB-RD variants correlate with distinct transcriptional signatures in vivo, we compared the striatal transcriptome of RarbR387C/+, RarbL402P/+, Rarb-/- and Rarb+/-mice with their littermate controls. We found that the heterozygous RARB-RD variants and the homozygous null allele affected a large subset of common genes, with putative direct RARB targets predominantly downregulated. Notably, the transcriptional impact of the RARB-RD variants was more profound than that of the null allele, regardless of zygosity. Additionally, transcriptional changes in RARB-RD mice extensively overlapped with those observed in mouse models of Huntingtons disease, suggesting shared mechanisms affecting neuronal survival in the striatum. We conclude that the p.R387C and p.L402P variants similarly compromise striatal integrity and function, likely through a DN mechanism. Progressive emergence of most neurologic deficits highlights a potential therapeutic window. Our results support the development of strategies aimed at silencing RARB-RD alleles.

neuroscience↗

bioRxiv2025

Success of GDNF-based treatment of Hirschsprung disease depends on NCAM1 signaling and various subtypes of enteric neural progenitors

Hirschsprung disease (HSCR) is a deadly congenital disorder where the enteric nervous system (ENS) is absent from the distal bowel. Current surgical treatment is generally life-saving but is often accompanied by long-term bowel problems and comorbidities. As alternative, we are developing a regenerative therapy based on rectal administration of Glial cell-derived neurotrophic factor (GDNF). We previously showed that administering GDNF enemas to HSCR mice soon after birth is sufficient to permanently induce a new ENS from tissue-resident neural progenitors. Here, we elucidate the underlying mechanism using single-cell transcriptomics, signal transduction inhibitors and genetic cell lineage tracing tools. We found that the neurogenic effect of GDNF is mediated by NCAM1 (Neural cell adhesion molecule 1), rather than by its canonical signaling receptor RET (Rearranged during transfection). We also unveiled the existence of multiple neuronal differentiation pathways that involve a larger than expected repertoire of tissue-resident neural progenitors, including a surprising one not derived from the usual neural crest. These data support feasibility of GDNF-based therapy in most human patients, even those bearing a RET variant. This work also has far-reaching implications for the choice of ENS progenitor source to use when developing cell transplantation-based therapeutic approaches.

neuroscience↗