Biology subjects

Henricsson, M.

Publications and source records attributed to Henricsson, M..

6 recordsLinked to original sources

bioRxiv2026

A pcyt-1 Allelic Series Reveals In Vivo Consequences of Reduced Phosphatidylcholine Synthesis in C. elegans

Phosphatidylcholine (PC) is the most abundant phospholipid in eukaryotic membranes and is synthesized in part via the rate-limiting enzyme PCYT1A. In humans, hypomorphic PCYT1A variants cause diverse disorders, including retinal dystrophy, lipodystrophy with fatty liver, and spondylometaphyseal dysplasia. To define how graded reductions in PC synthesis affect organismal physiology, we generated and characterized a series of mutant alleles in the Caenorhabditis elegans homolog pcyt-1, including variants corresponding to disease-causing human mutations, as well as an auxin-inducible degradation (AID) allele. We identify a clear allelic hierarchy. The V146M variant is embryonic lethal, whereas A97T is largely benign. P154A is temperature-sensitive, and C211Y causes growth delay, reduced brood size, sterility, and lengthened lifespan at standard temperature. Phenotypes of C211Y are rescued by choline, CDP-choline, or phosphatidylcholine supplementation, supporting reduced enzymatic function. Lipidomic profiling reveals that decreased PC synthesis consistently increases long-chain polyunsaturated fatty acids (LCPUFAs) in both PCs and PEs at the expense of shorter saturated species, without markedly altering the PC/PE ratio at 20{degrees}C. At elevated temperature, the P154A variant exhibits protein instability and a decreased PC/PE ratio. Despite significant lipid remodeling, canonical ER, mitochondrial, and metabolic stress GFP-based reporters are not activated; only the oxidative stress response is elevated, consistent with increased peroxidation-prone LCPUFAs in the pcyt-1 mutant. Acute auxin-induced degradation of PCYT-1 in larvae causes developmental arrest, while acute PCYT-1 degradation in adults disrupts oogenesis, demonstrating a continuous requirement for PC synthesis. Together, these findings establish a functional pcyt-1 allelic series and show that limiting PC synthesis drives compensatory remodeling toward LCPUFA-enriched membranes while rendering the germline particularly vulnerable.

cell biology↗

bioRxiv2025

Forward Genetics Identifies ptr-18 and Other Genes as Developmental Regulators of the Four-Cell Tail Tip in C. elegans

In C. elegans, the epidermis and its overlying extracellular matrix form a primary protective barrier, functioning as the first line of defense against environmental factors. To properly develop those cellular boundaries, a tightly controlled interaction of many molecules and pathways is needed. Mutant alleles of paqr-2 and iglr-2 (lipid homeostasis), dpy-21 (membrane trafficking), and sma-1 (actin-binding spectrin) result in hermaphrodite tail tip defects suggesting that this simple four-cell structure can serve as a sensitive model for the identification of pathways responsible for the establishment of cellular boundaries. With this in mind, we performed a small forward genetics screen of [~]800 ethyl methanesulfonate-mutagenized haploid genomes and identified 21 mutants with a tail end defective (Ted) phenotype. Whole genome sequencing of these mutants identified mutations in genes encoding either structural constituents of the cuticle itself (mostly collagen genes) or protein with regulatory functions. By using CRISPR/Cas9 we confirmed six novel alleles of ptr-18, paqr-2, nab-1, ncam-1, vab-9 and efn-4. We further characterized the loss of function allele ptr-18(et70), which encodes a patch domain-containing (PTCHD) protein homologous to human PTCHD1. ptr-18(et70) has a significant effect on growth and development of the worms, while also increasing membrane permeability. Lipidomics analysis revealed no major alterations in membrane lipid composition, implicating cuticle defects as the primary cause of the observed permeability phenotype. Article summaryWe performed a forward genetics screen to identify hermaphrodite C. elegans mutants with a tail end defect with the goal to discover membrane and morphogenesis regulators. The screen of 800 haploid genomes revealed 21 tail end defective mutants, including 8 novel alleles of interesting regulator protein. We conclude that the tail tip phenotype can be useful in discovery of new pathways and interactions during development.

cell biology↗

bioRxiv2024

A fat-2(wa17) suppressor screen in C. elegans reveals genetic adaptations to polyunsaturated fatty acid deficiency

Polyunsaturated fatty acids (PUFAs) are essential for mammalian health and function as membrane fluidizers and precursors for signaling lipids though the primary essential function of PUFAs within organisms has not been established. Unlike mammals who cannot endogenously synthesize PUFAs, C. elegans can de novo synthesize PUFAs starting with the {Delta}12 desaturase FAT-2 which introduces a second double bond to monounsaturated fatty acids to generate the PUFA linoleic acid. FAT-2 desaturation is essential for C. elegans survival since fat-2 null mutants are non-viable; the near-null fat-2(wa17) allele synthesizes only small amounts of PUFAs and produces extremely sick worms. Using fluorescence recovery after photobleaching (FRAP), we found that the fat-2(wa17) mutant has rigid membranes and can be efficiently rescued by dietarily providing various PUFAs, but not by fluidizing treatments or mutations. With the aim of identifying mechanisms that compensate for PUFA-deficiency, we performed a forward genetics screen to isolate novel fat-2(wa17) suppressors and identified four internal mutations within fat-2, and six mutations within the HIF-1 pathway. The suppressors increase PUFA levels in fat-2(wa17) mutant worms and additionally suppress the activation of the daf-16, UPRer and UPRmt stress response pathways that are active in fat-2(wa17) worms. We hypothesize that the six HIF-1 pathway mutations, found in egl-9, ftn-2, and hif-1 all converge on raising Fe2+ levels and in this way boost desaturase activity, including that of the fat-2(wa17) allele. We conclude that PUFAs cannot be genetically replaced and that the only genetic mechanism that can alleviate PUFA-deficiency do so by increasing PUFA levels.

cell biology↗

bioRxiv2023

Adipocyte PI3K links adipostasis with insulin secretion through an adipoincretin effect

Insulin secretion is governed by insulin-PI3K signaling. Resolving the mechanism of this feedback is necessary to understand how insulin operates. Mice lacking the insulin receptor, or AKT1 and AKT2 in adipocytes, are severely lipoatrophic. Thus, the role of adipocyte insulin-PI3K signaling in the control of insulin secretion remains unknown. Using adipocyte- specific PI3K knockout mice (PI3KAdQ) and a panel of isoform-selective PI3K inhibitors, we have found that PI3K and PI3K{beta} activities are functionally redundant in adipocyte insulin signaling. PI3K{beta}-selective inhibitors had no effect on adipocyte AKT phosphorylation in control mice but blunted AKT phosphorylation specifically in adipocytes of PI3KAdQ mice, demonstrating adipocyte-selective inhibition of PI3K signaling. Adipocyte-selective PI3K inhibition increased serum FFA and potently induced insulin secretion. We name this phenomenon the adipoincretin effect. The adipoincretin effect was dissociated from blood glucose and blood glucose counterregulatory response. The contribution of lipolysis, lipid, and amino acid metabolism, and selected adipokines to the adipoincretin effect has been investigated. We conclude that basal insulin secretion is chiefly controlled by adipocyte PI3K signaling through the adipoincretin effect. This phenomenon reveals an essential role for adipocyte insulin-PI3K signaling in linking the rates of adipose tissue lipolysis with baseline insulin secretion during fasting.

physiology↗

bioRxiv2023

TREM2 is downregulated by HSV1 in microglia and involved in antiviral defense in the brain

Immunological control of viral infection in the brain is essential for immediate protection, but also for long-term maintenance of brain integrity. As the primary resident immune cell of the brain, microglia protect against viral infections through key macrophage functions, including release of the antiviral type I interferons (IFN-I) and clearance of infected cells. Microglia express the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS), which can bind viral DNA leading to signaling through stimulator of interferon genes (STING), and downstream immune activation. Here we report that herpes simplex virus (HSV) 1 infection of microglia leads to activation of IFN-I genes and pro-inflammatory cytokines. However, HSV1 also down-regulated expression of a subset of genes, including genes in the pathway engaged by the microglial receptor triggering receptor expressed on myeloid cells-2 (TREM2). Knockdown experiments revealed that TREM2 is important for viral activation of cGAS-STING signaling in microglia, induction of IFN-I, and phagocytosis of HSV1 infected neurons. Consequently, TREM2 depletion increased susceptibility to HSV1 infection in human microglia-neuron co-cultures and mice in vivo. Mechanistically, we show that TREM2 is essential for phosphorylation of STING, and downstream activation of the IFN-inducing transcription factor IRF3. We conclude that TREM2 is a novel component of the antiviral immune response in microglia, crucial for immediate host defense against HSV1 in the brain. Since both TREM2 loss-of-function mutations and HSV1 serological status are linked to development of Alzheime[r]s disease (AD), this work opens the question whether defects in TREM2 could predispose to impaired viral clearance and post-infection pathological neurological changes.

immunology↗

bioRxiv2021

Sphingosine 1-Phosphate Mediates Adiponectin Receptor Signaling Essential For Lipid Homeostasis And Embryogenesis

Cells and organisms require proper membrane composition to function and develop. Phospholipids are the major component of membranes and are primarily acquired through the diet. Given great variability in diet composition, cells must be able to deploy mechanisms that correct deviations from optimal membrane composition and properties. Here, using lipidomics and unbiased proteomics, we found that the embryonic lethality in mice lacking the fluidity regulators Adiponectin Receptors 1 and 2 (AdipoR1/2) is associated with aberrant high saturation of the membrane phospholipids. Using mouse embryonic fibroblasts (MEFs) derived from AdipoR1/2-KO embryos, human cell lines and the model organism C. elegans we found that, mechanistically, AdipoR1/2-derived sphingosine 1-phosphate (S1P) signals in parallel through S1PR3-SREBP1 and PPAR{gamma} to sustain the expression of the fatty acid desaturase SCD and maintain membrane properties. Thus, our work identifies an evolutionary conserved pathway by which cells and organism achieve membrane homeostasis and adapt to a variable environment.

cell biology↗