Biology subjects

Levi, N.

Publications and source records attributed to Levi, N..

4 recordsLinked to original sources

bioRxiv2025

A neural entero-pancreatic pathway that regulatesinsulin secretion and glucose tolerance

Signals from the gut enhance pancreatic secretion of insulin and thus influence glucose metabolism. This phenomenon, known as the incretin effect, is thought to be mediated by hormones secreted from enteroendocrine cells. The endocrine model, however, does not fully capture the complexity of gut-pancreas interactions. Anatomical studies identified a direct neural connection between the gut and the pancreas, known as the entero-pancreatic plexus. The role of this connection in regulating glucose metabolism remains unknown. Here we identify and functionally characterize a subpopulation of nitridergic myenteric neurons in the proximal duodenum that project directly to the pancreas. The anatomical and transcriptomic signature of these neurons places them downstream of glutamatergic and enkephalinergic enteric interneurons that indirectly respond to luminal nutrient stimuli. Their axonal projections to the pancreas contact neuro-insular ganglia and reach into the islet parenchyma. When activated chemogenetically, this circuit increases Ca2+ responses in pancreatic beta cells, enhances insulin secretion, and improves glucose tolerance in vivo. Our findings reveal a direct gut-pancreas neural pathway that complements incretin signaling in potentiating insulin secretion. This unexpectedly strong neuronal modulation of beta cell function could be harnessed to improve glycemic control in diabetes.

neuroscience↗

bioRxiv2023

CTCF supports melanoma cell migration by repressing cholesterol biosynthesis

CTCF is a key factor in three-dimensional chromatin folding and transcriptional control that was found to affect cancer cell migration by a mechanism that is still poorly understood. To identify this mechanism, we used mouse melanoma cells with a partial loss of function (pLoF) of CTCF. We found that CTCF pLoF inhibits cell migration rate while leading to an increase in the expression of multiple enzymes in the cholesterol biosynthesis pathway along with an elevation in the cellular cholesterol levels. Inhibition of cholesterol synthesis in CTCF pLoF cells restored the cellular migration rate, suggesting that CTCF supports cell migration by suppressing cholesterol synthesis. Detailed analysis of the promoter of Hmgcs1, an early enzyme in the cholesterol synthesis pathway, revealed that CTCF enables PRC2 recruitment to the promoter and deposition of H3K27me3 to prevent SREBP2 binding and activation of transcription. By this mechanism CTCF fine-tunes cholesterol levels to support cell migration. Notably, genome wide association studies suggest a link between CTCF and cholesterol-associated diseases, thus CTCF emerges as a new regulator of cholesterol biosynthesis.

genomics↗

bioRxiv2023

CTCF is essential for proper mitotic spindle structure and anaphase segregation

Mitosis is an essential process in which the duplicated genome is segregated equally into two daughter cells. CTCF has been reported to be present in mitosis but its importance for mitotic fidelity remains to be determined. To evaluate the importance of CTCF in mitosis, we tracked mitotic behaviors in wild type and two different CTCF CRISPR-based genetic knockdowns. We find that knockdown of CTCF results in prolonged mitoses and failed anaphase segregation via time lapse imaging of SiR-DNA. CTCF knockdown did not alter cell cycling or the mitotic checkpoint, which was activated upon nocodazole treatment. Immunofluorescence imaging of the mitotic spindle in CTCF knockdowns revealed disorganization via tri/tetrapolar spindles and chromosomes behind the spindle pole. Imaging of interphase nuclei showed that nuclear size increased drastically, consistent with failure to divide the duplicated genome in anaphase. Population measurements of nuclear shape in CTCF knockdowns do not display decreased circularity or increased nuclear blebbing relative to wild type. However, failed mitoses do display abnormal nuclear morphologies relative to successful mitoses, suggesting population images do not capture individual behaviors. Thus, CTCF is important for both proper metaphase organization and anaphase segregation which impacts the size and shape of the interphase nucleus.

cell biology↗

bioRxiv2020

Reduced nuclear lamin A/C enhances cancer cell squeezing through rigid barriers, does not facilitate endothelial crossing, and impairs experimental metastasis

The mechanisms by which the nuclear lamina of tumor cells controls their migration and survival are poorly understood. Lamin A and its variant lamin C are key nuclear lamina proteins that control nucleus stiffness and chromatin conformation. Downregulation of lamin A/C levels in two metastatic lines, B16F10 melanoma and E0771 breast carcinoma, facilitated cell squeezing through rigid pores, elevated nuclear deformability and reduced heterochromatin. Unexpectedly, the transendothelial migration of both cancer cells in vitro and in vivo, through lung capillaries, was not elevated by lamin A/C knockdown. Both cancer cells with lamin A/C knockdown grew normally in primary tumors and in vitro on rigid surfaces. Strikingly, however, both lamin A/C deficient melanoma and breast cancer cells grew poorly in 3D spheroids expanded in soft agar cultures. Experimental lung metastasis of both lamin A/C knockdown cells was also markedly reduced. Taken together, our results suggest that high content of lamin A/C in multiple cancer cells promotes cancer cell survival and ability to generate lung metastasis without compromising cancer cell emigration from lung vessels.

cancer biology↗