Kamal Rahmouni

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas that arise from Schwann cells and lack effective therapies. RABL6A is an oncogenic Rab-like GTPase whose expression is associated with worse survival in many human cancers. It is required for human MPNST cell survival, and its expression is dramatically increased in patient MPNSTs compared to benign precursor lesions. Methods: To model elevated expression of RABL6A in vivo, we developed transgenic mice expressing Cre-inducible Rabl6a. These Rabl6a-tg mice express the murine Rabl6a cDNA with a 5′ hemagglutinin [HA] epitope sequence downstream of a CMV enhancer and separated by a lox–stop–lox cassette. Double transgenic DhhCre; Rabl6a-tg mice were generated to achieve Schwann-cell specific Cre expression from the Desert hedgehog (Dhh) promoter. De novo MPNSTs were induced by CRISPR editing of Nf1, Ink4a, and Arf genes in the mouse sciatic nerve. Results: Cre-dependent expression of transgenic Rabl6a was verified at the mRNA and protein levels in Cre-positive mouse embryo fibroblasts and tissues. Increased Rabl6a expression in DhhCre; Rabl6a-tg mice had no effect on de novo MPNST initiation but significantly accelerated tumor progression relative to DhhCre control mice. The Rabl6a phenotype was associated with increased tumor angiogenesis but not proliferation. Interestingly, many MPNSTs in the DhhCre background exhibited varying levels of rhabdomyoblastic (RMB) features. That immature muscle cell phenotype is a hallmark of malignant Triton tumors, a rare histological variant of human MPNSTs associated with worse outcomes. Conclusions: These data provide direct evidence that Rabl6a is a functional driver of MPNSTs while establishing Rabl6a-tg mice as a suitable model for investigating Rabl6a’s role in other lethal RABL6A-high tumors.

This study combines AI modeling and experimental validation to define key structural features and receptor interactions of the BBSome complex. The analysis identifies BBS1 and BBS9 as central hubs, reveals how the BBS1 ^M390R mutation destabilizes the complex, and uncovers novel contacts with various receptors including those involved in metabolic regulation. These findings provide a predictive framework linking BBSome structure to ciliary signaling and metabolic regulation in Bardet–Biedl syndrome.

Background The outer mitochondrial Rho GTPase 1, MIRO1, mediates mitochondrial motility within cells, but implications for vascular smooth muscle cell (VSMC) physiology and its roles in vascular diseases, such as neointima formation following vascular injury are widely unknown. Methods Carotid ligation was performed in an in vivo model of selective Miro1 deletion in smooth muscle cells. VSMC proliferation during the cell cycle and molecular mechanisms of smooth muscle cell proliferation were explored in cultured aortic VSMCs by imaging mitochondrial positioning and cristae structure and assessing the effects on ATP production, metabolic function, and interactions with components of the electron transport chain (ETC). MIRO1 expression was also analyzed in human coronary arteries, and its function was assessed via knockdown in human coronary artery VSMCs. Results MIRO1 was highly expressed in VSMCs within human atherosclerotic plaques. MIRO1 facilitated VSMC proliferation and neointima formation by regulating mitochondrial positioning and PDGF-stimulated ATP production and respiration, critical for cell-cycle progression at G1/S. Deletion of Miro1 disrupted mitochondrial cristae structure, diminished ETC complex I activity, and impaired supercomplex formation. Notably, restoring MIRO1 function with expression of wild type MIRO1 recovered proliferation and ATP production and respiration, whereas a mutant lacking EF hands, which are essential for mitochondrial motility, only partially rescued these effects. MIRO1 knockdown in human coronary artery VSMCs confirmed its pivotal role in mitochondrial function and VSMC proliferation. Conclusions This study highlights two key mechanisms by which MIRO1 regulates VSMC proliferation. First, it maintains ATP synthesis by preserving mitochondrial cristae integrity. Second, its Ca2+-dependent EF hands enable ATP-dependent mitochondrial positioning. By linking mitochondrial motility and energy production to VSMC physiology, these findings position MIRO1 as a critical regulator of vascular remodeling and a potential target for therapeutic interventions.

The autonomic networks of the central nervous system tightly coordinate metabolic and cardiovascular functions. The frequent coexistence of metabolic and cardiovascular disorders suggests cross talk between neural circuits governing energy balance and cardiovascular regulation. In this study, we used trans-neuronal tracing to define the higher-order neurons involved in the coordination of cardiometabolic regulation in mice. We identified several nuclei that contain neurons associated with a cardiovascular organ (kidney) and metabolic tissues (brown adipose tissue [BAT] or liver), with substantial overlap across regions. Co-projecting neurons (kidney-BAT or kidney-liver) were observed in areas including the cortical, hypothalamic, midbrain, and brainstem regions. Analysis of soma size revealed regional and organ-specific differences, with some nuclei exhibiting multiple morphological phenotypes. Notably, soma size distributions differed significantly between kidney- and BAT-projecting neurons in the motor cortex and locus coeruleus, but not in the paraventricular nucleus or lateral hypothalamus. These findings indicate that while cardiometabolic control involves overlapping neuronal populations, morphological specialization may distinguish neurons regulating cardiovascular versus metabolic functions. Together, this work provides anatomical evidence supporting the integrative organization of autonomic networks that coordinate cardiovascular and metabolic regulation.

Roux-en-Y gastric bypass in obese mice triggered markers of vagal nerve injury, reduced Glp1r-expressing vagal afferents, and lowered Glp1r mRNA in the nodose ganglion. Nerve injury experiments reproduced these effects. Despite reduced receptor expression, GLP1R agonist-evoked vagal firing was exaggerated after RYGB or vagal injury. Overall, the findings indicate RYGB causes vagal neuropathy with diminished Glp1r expression but heightened GLP1 sensitivity.

Obesity continues to be a major global health crisis, contributing to the rising prevalence of metabolic disorders such as type 2 diabetes, cardiovascular disease, and certain cancers. Central to the regulation of energy homeostasis is the adipocyte-derived hormone leptin, which serves as a key afferent signal to the central nervous system to suppress food intake, enhance energy expenditure, and maintain glucose balance. Since its discovery over three decades ago, a wealth of research has illuminated the molecular, cellular, and physiological mechanisms through which leptin exerts its metabolic effects. These foundational studies have delineated the neural circuits, particularly within the hypothalamus and brainstem, that integrate leptin signaling to co-ordinate complex metabolic responses. This review provides a comprehensive synthesis of the current understanding of leptin’s metabolic actions, with an emphasis on the intracellular signaling cascades that mediate leptin receptor activation. We also highlight the diverse neuronal populations and brain regions that contribute to leptin’s regulatory roles.

Chronic overactivation of neurohormonal systems is the principal driver of adverse cardiac remodeling following myocardial infarction (MI). Recent data suggest that ablating cardiac afferent neurons in rats attenuates left ventricular (LV) remodeling following MI by blocking this overactivation. Our lab has shown that acid-sensing ion channels (ASICs) are highly expressed in cardiac afferents and may sense myocardial acidosis. We hypothesized that genetic deletion of ASICs might abrogate disadvantageous remodeling after MI by disrupting afferent signaling pathways otherwise resulting in overactivation of neurohormonal responses. To test this hypothesis, we induced MI by coronary artery ligation in wild type (WT) and ASIC3 ^-/- mice and assessed cardiac remodeling by serial echocardiography. We found that ASIC3 ^-/- mice had less LV dilation relative to MI size, increased LV mass, and increased stroke volume compared to WT mice after MI. To investigate a potential role of the autonomic nervous system, we measured renal and splanchnic sympathetic nerve activity, heart rate and systolic blood pressure variability (sBPV), and hemodynamic responses to atropine and propranolol. In addition, we assessed baroreceptor-heart rate and baroreceptor-renal sympathetic nerve activity (RSNA) reflex function. Following MI, ASIC3 ^-/- mice had lower baroreceptor-RSNA reflex sensitivity than WT mice, associated with elevated sBPV. Importantly, sBPV correlated significantly with post-MI changes in LV mass in ASIC3 ^-/- but not WT mice. Our data shows that ASIC3 plays an important role in cardiac remodeling after MI potentially via modulation of baroreflex sensitivity and sBPV. ASIC3 may be further investigated as a potential therapeutic target in heart failure.