Biology subjects

Roger, C.

Publications and source records attributed to Roger, C..

5 recordsLinked to original sources

bioRxiv2025

Lipid transport is necessary for neocortical lamination

We previously described the Alkuraya-Ku[c]inskas syndrome, a disorder associated with biallelic variants in BLTP1 (bridge-like lipid transfer protein), a.k.a. KIAA1109. The majority of probands die perinatally with corpus callosum agenesis, ventriculomegaly and arthrogryposis. Homozygous ablation of mouse Bltp1 resulted in similar preweaning lethality. Here, we describe ten novel patients expanding the characterization of this syndrome at the mild end of the phenotypic spectrum. To model this syndrome, we engineered Emx1-Cre-mediated conditional knockouts (cKO) in which Bltp1 expression is only removed in cortical and hippocampal neurons. This restricted ablation of Bltp1 recapitulated the preweaning lethality observed in the constitutional knockouts, suggesting that lack of BLTP1 expression in neurons is sufficient to cause death. Homozygous cKO presented a complete agenesis of the corpus callosum, a smaller anterior commissure, a malformed hippocampus and a reduced thickness of the cortical plate with a complete lack of defined structural layers and absence of radial glial and intermediate neural progenitors and mature neurons. As BLTP1 was shown to be a barrel-shaped tube containing lipids, we compared the amount of lipid species in the cKO and their control littermates cortexes. We observed significant depletions of ether-linked phosphatidylethanolamines and triglycerides and accumulations of sphingomyelins and hexosylceramides in cKOs. Our results are consistent with the recent description of BLTP1 as a tubular protein that transports phospholipids between the endoplasmic reticulum and the plasma membrane. They suggest that non-vesicular lipid transport is essential for neocortical and cerebellar lamination. Consistent with a BLTP1 role in cortex development we show that heterozygous carriers of a BLTP1 truncation variant presented a decrease in peripheral cortical grey matter suggesting an autosomal dominant inheritance pattern beside the already described autosomal recessive.

genetics↗

bioRxiv2025

Estrogen Receptors/E2F1/CDKN3 Axis Protects from UV-induced Skin Cancers in Females

Men have a significantly higher risk of developing cutaneous squamous cell carcinoma (SCC) compared to women, but models and comprehensive analysis of signaling pathways highlighting this sexual dimorphism are missing. In this study, we display a UV-induced SCC model in hairless mice recapitulating this sex difference, with enhanced SCC development in males. While UV-induced DNA damage is similar between sexes, we uncovered sex-specific responses in epidermal cell proliferation and differentiation. Using global transcriptional profile analyses, we identified E2F transcription factors as key sex-specific markers involved in the proliferative response to UV. Notably, E2F1/2, along with their target gene CDKN3, were selectively downregulated in female mice and human epidermis following UV exposure. Mechanistically, UV-induced and sex-specific modulation of E2F1 and CDKN3 expression is mediated by Estrogen Receptors. Lastly, low levels of CDKN3 in head and neck SCC are observed exclusively in female patients correlating with better prognosis. These findings shed new light on fundamental mechanisms protecting women from cancer after carcinogen exposure and could lead to better sex-targeted preventive and therapeutic strategies in SCC and other malignancies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/637819v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@7edcc5org.highwire.dtl.DTLVardef@d0215corg.highwire.dtl.DTLVardef@3e248forg.highwire.dtl.DTLVardef@1d25cb9_HPS_FORMAT_FIGEXP M_FIG C_FIG Sex differences in UV-Induced cutaneous Squamous Cell Carcinoma: key insights into female cancer protection

cancer biology↗

bioRxiv2024

CDK4 inactivation balances resistance to apoptosis with heightened metabolic sensitivity in triple negative breast cancer cells

The shift in the energetic demands of proliferating cells during tumorigenesis requires intense crosstalk between the cell cycle and metabolism. Beyond their role in cell proliferation, cell cycle regulators also modulate intracellular metabolism in normal tissues. However, in the context of cancer, where CDK4 is upregulated or stabilized, the metabolic role of CDK4 is barely understood. Using both genetic and pharmacological approaches, we aimed to determine the metabolic role of CDK4 in TNBC cells. Unexpectedly, deletion of CDK4 only slightly reduced triple-negative breast cancer (TNBC) cell proliferation and allowed tumor formation in vivo. Furthermore, proapoptotic stimuli failed to induce appropriate cell death in TNBC cells with CDK4 depletion or long-term CDK4/6 inhibitor treatment. Mechanistically, CDK4 enhances mitochondria-ER contact (MERC) formation, thus promoting mitochondrial fission and ER-mitochondrial calcium signaling. Phosphoproteomic analysis also revealed a role for CDK4 in regulating PKA activity at MERCs to sustain ER-mitochondrial calcium signaling. This proper CDK4-mediated mitochondrial calcium signaling is then required for metabolic flexibility of TNBC cells. Taken together, these results demonstrate that CDK4 inhibition leads to cell death resistance, inhibiting mitochondrial apoptosis and functions through attenuated MERCs formation and ER-mitochondrial calcium signaling in TNBC. Overall, this study provides new insights into the mechanisms of TNBC resistance to CDK4/6i therapy and paves the way to explore potential synergistic therapeutic targeting MERCs-associated metabolic shifts. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=158 HEIGHT=200 SRC="FIGDIR/small/613455v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@36f496org.highwire.dtl.DTLVardef@1f3aa1dorg.highwire.dtl.DTLVardef@258d49org.highwire.dtl.DTLVardef@15ed9a6_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

CDK4 deletion in mice prevents fat accumulation and increases endurance capacity through activation of estrogen related receptor (ERR)driven oxidative metabolism in skeletal muscle

Cyclin-dependent kinase 4 (CDK4) canonical role is to control cell cycle progression from G1 to S phases. However, recent studies reported that CDK4 regulates energy metabolism in non-proliferating cells such as hepatocytes or adipocytes. The objective of our work is to study CDK4 function in skeletal muscle using a model of mice lacking CDK4 (cdk4-/-). By coupling treadmill running to indirect calorimetry, we show that cdk4-/- mice display improved endurance and higher capacity to use fat as fuel during exercise. Isolated muscles lacking CDK4 are more resistant to fatigue in response to repeated contractions and have increased oxidative capacity and mitochondrial content compared to cdk4+/+ muscles. Transcriptomic analysis reveals upregulation of genes controlled by the nuclear receptors estrogen-related receptors (ERRs) in cdk4-/- skeletal muscle, associated with elevated levels of the ERR co-activator PGC1a. Supporting in vivo results, C2C12 myotubes treated with a CDK4 inhibitor have increased mitochondrial oxygen consumption, PGC1 expression and ERR transcriptional activity measured by a luciferase reporter. In normal housing conditions, cdk4-/- mice show an increased basal metabolic rate and are resistant to weight gain and fat accumulation. In conclusion, our study uncovers a role for CDK4 in the control of skeletal muscle metabolism. Moreover, CDK4 inhibition may be an alternative strategy against obesity-associated metabolic disorders.

physiology↗

bioRxiv2017

Temporal metacognition as the decoding of self-generated brain dynamics

Metacognition, the ability to know about ones thought process, is self-referential. Here, we combined psychophysics and time-resolved neuroimaging to explore metacognitive inference on the accuracy of a self-generated behavior. Human participants generated a time interval and evaluated the signed magnitude of their temporal production. We show that both self-generation and self-evaluation relied on the power of beta oscillations ({beta}; 15-40 Hz) with increases in early {beta} power predictive of increases in duration. We characterized the dynamics of {beta} power in a low dimensional space ({beta} state-space trajectories) as a function of timing and found that the more distinct trajectories, the more accurate metacognitive inferences were. These results suggest that {beta} states instantiates an internal variable determining the fate of the timing networks trajectory, possibly as release from inhibition. Altogether, our study describes oscillatory mechanisms for timing, suggesting that temporal metacognition relies on inferential processes of self-generated dynamics.

neuroscience↗