Biology subjects

Stuhlmann, H.

Publications and source records attributed to Stuhlmann, H..

5 recordsLinked to original sources

bioRxiv2026

SHP2 binds directly to SOS1 to enable RAS activation

The protein-tyrosine phosphatase SHP2 (PTPN11) regulates growth factor- and cytokine-induced RAS/ERK MAP kinase (MAPK) pathway activation, and aberrant SHP2 function causes developmental disorders and cancer1-5. It is widely believed that the catalytic activity of SHP2 is essential for pathway activation1,4,6-8. This view has shaped our interpretation of how germline PTPN11 mutations cause Noonan Syndrome (NS) and NS with Multiple Lentigines (NS-ML)2,9 and how somatic mutations contribute to myeloproliferative neoplasms and solid tumors1. Here we identify a previously undetected, protein-tyrosine phosphatase (PTP) activity-independent mechanism that revises our understanding of how SHP2 promotes RAS/ERK activation. We find that certain mutations of the nucleophilic cysteine that abolish catalytic activity still promote RAS/ERK pathway activation in normal and neoplastic mammalian cells, zebrafish embryos, and mice. Structural studies show that the SHP2 PTP domain binds directly to the Son of Sevenless 1 (SOS1) Dbl homology (DH) domain. Proximity labeling and super-resolution microscopy demonstrate that SHP2/SOS1 interaction occurs in cells and facilitates SOS1 translocation to the plasma membrane to form clusters. Our results overturn decades of dogma on SHP2 regulation of the RAS/ERK pathway and provide new insights into the mechanism of action of disease-associated PTPN11 mutations.

Cancer Biology↗

bioRxiv2025

Aldehyde dehydrogenase protein: a placental glycogen trophoblast marker suitable to monitor placental pathologies in mouse models

This study focuses on developing new approaches to identify and quantify glycogen trophoblast cells in the placenta. Due to limitations with currently available methods, alternative markers for these cells are being explored. Here we report on one promising candidate, Aldh1a3, a gene that was recently shown to be expressed in the mouse placenta only in glycogen trophoblast cells and their progenitors. Our study validates ALDH1A3 protein as glycogen trophoblast marker in the mouse placenta with high specificity when compared to CDKN1C (p57KIP2). This marker will be useful for the isolation of the glycogen trophoblast subpopulation and facilitate examining its function in placental programming and understanding its role in pathological pregnancy models. Furthermore, trophoblast giant cells with high expression of ALDH1A3 were detected in the decidua of human term placentas. These were interspersed with extravillous interstitial trophoblast cells or were located distal of the interstitial trophoblast layer of the decidua basalis.

developmental biology↗

bioRxiv2024

miR-126 modulates neural progenitor cell development

Noncoding microRNAs (miRNAs) play important roles in controlling signaling pathways by targeting multiple genes and altering their expression levels. MiR-126 is a known endothelial-specific miRNA that regulates vascular integrity and angiogenesis by enhancing proangiogenic actions of VEGF and FGF. MiR-126 is also expressed in several stem cell compartments, including embryonic stem cell (ESC) and hematopoietic stem/progenitor cells (HSPC) where it regulates cell differentiation and quiescence. Here we show that miR-126 is expressed as well in neural progenitor cells where it regulates cell differentiation by targeting genes of the IGF1R signaling pathway including IRS1, PI3K and AKT. Moreover, Hoxa9 and IGF-1 expression by neural progenitor cells is upregulated when miR-126 expression levels are reduced. Our data, implicating a role for miR-126 in manipulating cell development, could open a window of opportunities for clinical purposes and therapeutic strategies to achieve controlling neural progenitor cell behavior. HighlightsO_LIKnockdown of miR-126 in neural progenitor cells increases cell proliferation C_LIO_LImiR-126 modulates expression levels of HoxA9 and known target genes involved in the IGF1R signaling pathway in neural progenitor cells C_LIO_LIOverexpression of miR-126 results in induced cell differentiation in neural progenitor cells C_LIO_LImiR-126 affects motor neuron development in the thoracic region of the spinal cord C_LIO_LIKnockdown of miR-126 expression results in increased IGF-1 expression C_LI

cell biology↗

bioRxiv2022

Single-cell RNA sequencing implicates venous endothelial cells as a source of VEGF-mediated neo-angiogenesis in neuroinflammation

Histopathological studies of multiple sclerosis (MS), a demyelinating disease of the central nervous system (CNS), and its animal model, experimental autoimmune encephalomyelitis (EAE), have found newly formed leaky vessels in demyelinated acute and chronic plaques, in addition to blood-brain barrier (BBB) damage in existing vessels, that exacerbate disease pathology by increasing infiltration of immune cells. Which vessel subtypes and signaling pathways generate these aberrant vessels is poorly understood. Using single-cell RNA-sequencing and in vivo validation, we find that transcriptome signatures of neo-angiogenesis arise in venous endothelial cells in both acute and chronic EAE, and correlate with upregulation in VEGF-A signaling. These neo-angiogenic markers are also increased in acute and chronic MS lesions. Treatment with a VEGF-A blocking antibody diminishes neo-angiogenic transcriptomic signatures and vascular proliferation in vivo, but does not restore BBB function or ameliorate significantly EAE pathology. Therefore, anti-angiogenic therapies in combination with immunomodulatory therapies may benefit MS progression.

neuroscience↗

bioRxiv2021

SARS-CoV-2 Infects Syncytiotrophoblast and Activates Inflammatory Responses in the Placenta

SARS-CoV-2 infection during pregnancy leads to an increased risk of adverse pregnancy outcomes. Although the placenta itself can be a target of virus infection, most neonates are virus free and are born healthy or recover quickly. Here, we investigated the impact of SARS-CoV-2 infection on the placenta from a cohort of women who were infected late during pregnancy and had tested nasal swab positive for SARS-CoV-2 by qRT-PCR at delivery. SARS-CoV-2 genomic and subgenomic RNA was detected in 23 out of 54 placentas. Two placentas with high virus content were obtained from mothers who presented with severe COVID-19 and whose pregnancies resulted in adverse outcomes for the fetuses, including intrauterine fetal demise and a preterm delivered baby still in newborn intensive care. Examination of the placental samples with high virus content showed efficient SARS-CoV-2 infection, using RNA in situ hybridization to detect genomic and replicating viral RNA, and immunohistochemistry to detect SARS-CoV-2 nucleocapsid protein. Infection was restricted to syncytiotrophoblast cells that envelope the fetal chorionic villi and are in direct contact with maternal blood. The infected placentas displayed massive infiltration of maternal immune cells including macrophages into intervillous spaces, potentially contributing to inflammation of the tissue. Ex vivo infection of placental cultures with SARS-CoV-2 or with SARS-CoV-2 spike (S) protein pseudotyped lentivirus targeted mostly syncytiotrophoblast and in rare events endothelial cells. Infection was reduced by using blocking antibodies against ACE2 and against Neuropilin 1, suggesting that SARS-CoV-2 may utilize alternative receptors for entry into placental cells.

cell biology↗