Biology subjects

Mondielli, G.

Publications and source records attributed to Mondielli, G..

3 recordsLinked to original sources

bioRxiv2024

Braf-mutant Schwann cells divert to a repair phenotype to induce congenital demyelinating neuropathy

RASopathies, rare congenital syndromes affecting multiple organ systems, often include peripheral neuropathy of unknown origin. While RASopathy-associated gene variants are proto-oncogenic, the impact of timing and mosaicism on pathogenicity remains poorly understood. Here, we investigate the links between Braf, a key mitogen-activated protein kinase (MAPK) effector, and peripheral neuropathy. By targeting Braf p.V600E, an oncogenic variant found in mosaic RASopathies, to embryonic Mpz-expressing cells in mice, we induced a congenital Charcot-Marie-Tooth-like degenerative neuropathy. This phenotype was characterized by hyperplastic nerves, hindlimb weakness, and unexpectedly reduced body size. Constitutively active Braf expanded a Jun+ Schwann cell repair state, impairing myelination and nerve homeostasis. To examine relevance to RASopathies, we differentiated patient-derived stem cells bearing the cardio-facio-cutaneous syndrome-associated BRAF p.Q257R variant into Schwann cells. Compared to wild-type controls, CFC-derived cells failed to acquire mature phenotypes, instead exhibiting progenitor or repair-type transcriptional profiles. Our findings implicate somatic mosaicism in the unresolved genetic heterogeneity of neuropathies and expand the candidate gene list for peripheral nerve disorders. Moreover, they reveal a MAPK-dependent mechanism linking neural crest-derived Schwann cell dysfunction to both body growth and nerve homeostasis, providing new insights into the mechanisms in RASopathy-associated neuropathy and potential therapeutic targets.

developmental biology↗

bioRxiv2023

D-Serine agonism of GluN1-GluN3 NMDA receptors regulates the activity of enteric neurons and coordinates gut motility

The enteric nervous system (ENS) is a complex network of diverse molecularly defined classes of neurons embedded in the gastrointestinal wall and responsible for controlling the major functions of the gut. As in the central nervous system, the vast array of ENS neurons is interconnected by chemical synapses. Despite several studies reporting the expression of ionotropic glutamate receptors in the ENS, their roles in the gut remain elusive. Here, by using an array of immunohistochemistry, molecular profiling and functional assays, we uncover a new role for D-serine (D-Ser) and non-conventional GluN1-GluN3 N-methyl D-aspartate receptors (NMDARs) in regulating ENS functions. We demonstrate that D-Ser is produced by serine racemase (SR) expressed in enteric neurons. By using both in situ patch clamp recording and calcium imaging, we show that D-Ser alone acts as an excitatory neurotransmitter in the ENS independently of the conventional GluN1-GluN2 NMDARs. Instead, D-Ser directly gates the non-conventional GluN1-GluN3 NMDARs in enteric neurons from both mouse and guinea-pig. Pharmacological inhibition or potentiation of GluN1-GluN3 NMDARs had opposite effects on mouse colonic motor activities, while genetically driven loss of SR impairs gut transit and fluid content of pellet output. Our results demonstrate the existence of native GluN1-GluN3 NMDARs in enteric neurons and open new perspectives on the exploration of excitatory D-Ser receptors in gut function and diseases.

neuroscience↗

bioRxiv2022

Multiple congenital malformations arise from somatic mosaicism for constitutively active Pik3ca signalling

Recurrent missense mutations of the PIK3CA oncogene are among the most frequent drivers of human cancers. These often lead to constitutive activation of its product p110, a phosphatidylinositol 3-kinase (PI3K) catalytic subunit. In addition to causing a broad range of cancers, the H1047R mutation is also found in affected tissues of a distinct set of congenital tumors and malformations. Collectively termed PIK3CA-related disorders (PRDs), these lead to overgrowth of brain, adipose, connective and musculoskeletal tissues and/or blood and lymphatic vessel components. Vascular malformations are frequently observed in PRD, due to cell-autonomous activation of PI3K signaling within endothelial cells. These, like most muscle, connective tissue and bone, are derived from the embryonic mesoderm. However, important organ systems affected in PRDs are neuroectodermal derivatives. To further examine their development, we drove the most common post-zygotic activating mutation of Pik3ca in neural crest and related embryonic lineages. Outcomes included macrocephaly, cleft secondary palate and more subtle skull anomalies. Surprisingly, Pik3ca-mutant subpopulations of neural crest origin were also associated with widespread cephalic vascular anomalies. Mesectodermal neural crest is a major source of non-endothelial connective tissue in the head, but not the body. To examine the response of vascular connective tissues of the body to constitutive Pik3ca activity during development, we expressed the mutation by way of an Egr2 (Krox20) Cre driver. Lineage tracing led us to observe new lineages that had normally once expressed Krox20 and that may be co-opted in pathogenesis, including vascular pericytes and perimysial fibroblasts. Finally, Schwann cell precursors having transcribed either Krox20 or Sox10 and induced to express constitutively active PI3K were associated with vascular and other tumors. These murine phenotypes may aid discovery of new candidate human PRDs affecting craniofacial and vascular smooth muscle development as well as the reciprocal paracrine signaling mechanisms leading to tissue overgrowth.

developmental biology↗