Biology subjects

Carvalho, C. E.

Publications and source records attributed to Carvalho, C. E..

2 recordsLinked to original sources

bioRxiv2026

A Dominant-Negative HIF-1 Isoform Protects Neuronal Development by Buffering the Response to Hypoxia in C. elegans

Animal cells respond to hypoxic stress through cell-autonomous stabilization of HIF-1, a conserved transcription factor that mediates adaptation to low-oxygen environments. Although HIF-1 is essential for viability under hypoxia, its persistent activation during development causes miswiring defects in the nervous system, raising the question of how developing neurons balance the pro-survival benefits of HIF-1 stabilization against these associated risks. Here we show that C. elegans neurons address this challenge by mobilizing an internal promoter within the hif-1 locus to generate a dominant-negative isoform, HIF-1c, which acts in the nucleus to limit HIF-1/AHA-1 heterodimer formation. This buffering mechanism supports proper neuronal migration, axon guidance, and circuit formation and its loss phenocopies the defects seen when the ubiquitous HIF-1 degradation pathway is disrupted, confirming that HIF-1c serves as a critical layer of protection for the developing nervous system against hypoxic-induced errors. Lastly, we identify the retinoblastoma protein LIN-35 as a modulator of HIF-1 signaling in worms via control of hif-1c expression. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/745244v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@3ad347org.highwire.dtl.DTLVardef@4fd4forg.highwire.dtl.DTLVardef@1928804org.highwire.dtl.DTLVardef@11fd1e1_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2018

Rapid nuclear exclusion of Hcm1 in aging Saccharomyces cerevisiae leads to vacuolar alkalization and replicative senescence

Yeast cells, like other higher eukaryotic cells, undergo a finite number of cell divisions before exiting the cell cycle due to the effects of aging. Here, we show that yeast aging begins with the nuclear exclusion of Hcm1 in young cells, resulting in loss of acidic vacuoles. Autophagy is required for healthy aging in yeast, with proteins targeted for turnover by autophagy directed to the vacuole. Consistent with this, vacuolar acidity is necessary for vacuolar function and yeast longevity. Using yeast genetics and immunofluorescence microscopy, we confirm that vacuolar acidity plays a critical role in cell health and lifespan, and is potentially maintained by a series of Forkhead Box (Fox) transcription factors. An interconnected transcriptional network involving the Fox proteins (Fkh1, Fkh2 and Hcm1) are required for transcription of v-ATPase subunits and vacuolar acidity. As cells age, Hcm1 is rapidly excluded from the nucleus in young cells, blocking the expression of Hcm1 targets (Fkh1 and Fkh2), leading to loss of v-ATPase gene expression, reduced vacuolar acidification, increased -syn-GFP vacuolar accumulation, and finally, diminished replicative lifespan (RLS). Loss of vacuolar acidity occurs about the same time as Hcm1 nuclear exclusion and is conserved; we have recently demonstrated that lysosomal alkalization similarly contributes to aging in C. elegans following a transition from progeny producing to post-reproductive life. Our data points to a molecular mechanism regulating vacuolar acidity that signals the end of RLS when acidification is lost.

genetics↗