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Timmermans, M.

Publications and source records attributed to Timmermans, M..

8 recordsLinked to original sources

Specification of embryonic shoot stem cells via a small RNA-driven morphogenic circuit

The specification of embryonic stem cells capable of self-renewing and differentiation into virtually any cell type, is one of the most consequential events in the development of a multicellular organism. Yet the mechanisms establishing embryonic stem cell fate remain poorly understood, particularly in monocotyledonous cereals. Using the classic mutant leafbladeless1-raggedseedling1, we show that the small RNA tasiARF acts as a primary epidermis-derived morphogenic signal that organizes shoot stem cell specification in the maize embryo. tasiARF restricts expression of the AUXIN RESPONSE FACTOR 3 (ARF3) transcription factor, which modulates cell wall mechanics and guides the differential localization of PIN-FORMED (PIN) auxin efflux carriers, establishing a localized auxin minimum permissive for stem cell fate. Interestingly, loss of this auxin minimum and the associated shoot stem cell defects in tasiARF-deficient embryos are buffered by natural variation at a quantitative trait locus (QTL) controlling expression of MICROTUBULE-ASSOCIATED PROTEIN 65-3 (MAP65-3), a critical factor determining cell division orientation, which reshapes auxin dynamics and restores stem cell specification, and is itself under tasiARF-ARF3 control. Thus, embryonic shoot stem cell specification in maize is governed by an intricate morphogenic circuit that couples small RNA-mediated positional information to a self-stabilizing network interdependently linking cell wall mechanics, auxin signaling, and cell division patterning. This mechanistic framework reveals the redeployment of an ancient small RNA pathway as a lineage-specific innovation to establish a conserved, stem cell-permissive low auxin environment within the divergent embryonic architecture of monocotyledonous cereals. More broadly, it identifies molecular entry points for the engineering of embryogenic competence and regeneration capacity for the improvement of cereal crops.

plant biology↗

A single-cell transcriptome atlas of the barley root apical meristem uncovers conserved and divergent roles of HvWOX5

Single-cell approaches have transformed plant developmental biology; however, cell-type-resolved resources for cereals remain limited. Here, we present a single-cell transcriptome atlas of the barley root apical meristem (RAM), which resolves 24 transcriptionally distinct cell populations. We assigned major root cell identities by integrating marker gene validation using Hybridization Chain Reaction (HCR) RNA fluorescence in situ hybridization and spatial transcriptomics with cross-species comparisons of published root atlases. Pseudotime analysis reconstructed developmental trajectories from the quiescent center to differentiating tissues, supporting the spatial and developmental organization of the atlas. We further demonstrated the utility of this resource by identifying HvWOX5 expression in the quiescent center and metaxylem and showing that HvWOX5 loss-of-function mutants displayed reduced root and meristem lengths, altered stem cell niche homeostasis, and disrupted metaxylem organization. Taken together, this atlas provides a framework for dissecting barley root development and identifies HvWOX5 as a key regulator of RAM organization and metaxylem patterning.

Plant Biology↗

Autophagy acts as a spatial organizer of cell-type-specific plant immunity

Effective plant immunity requires precise spatial coordination of immune responses across cell-types to restrict pathogens while preventing tissue damage, yet the intracellular pathways that organize this spatial architecture remain unknown. Here we show that autophagy serves as a spatial coordinator of immunity, partitioning and calibrating immune strategies across tissues during Pseudomonas syringae infection in Arabidopsis thaliana. Combining single-cell transcriptomics, cell-type-specific complementation, and live-cell imaging, we uncover distinct and opposing roles of autophagy across tissues. In guard cells, autophagy promotes pathogen-induced stomatal reopening by suppressing abscisic acid (ABA) signalling in part via autophagic turnover of the guard cell ABA receptor PYL4. In contrast, in mesophyll cells, autophagy restricts immune activation while simultaneously enabling effective immune execution: its loss enhances EDS1-PAD4-ADR1 pathway expression yet compromises PTI outputs. Mechanistically, bacterial infection triggers autophagic EDS1 turnover, supporting a model in which controlled EDS1 recycling facilitates HR elicitation. Cell-type-specific complementation reveals that PTI competence may involve coordinated autophagy across tissues, whereas mesophyll-autonomous autophagy is partially sufficient for HR execution. Together, these findings establish a framework in which spatial control of proteostasis orchestrates multicellular immune coordination, with broad implications for understanding how conserved degradation pathways regulate layered immunity across organisms.

plant biology↗

An ancient alkalinization factor informs Arabidopsis root development

The power of hydrogen (pH) regulates virtually all cellular activities. In both plants and animals, cell-to-cell variations in pH correlate with key developmental transitions1-5, yet the underlying regulators and associated functions remain elusive. Here, we report that members of the REMORIN (REM) protein family function as inhibitors of the H+-ATPases thereby promoting extracellular pH (pHe) alkalinization. This, in turn, regulates various cell surface processes, including steroid hormone signaling, and coordinates developmental transitions in the Arabidopsis thaliana root. Inhibition of H+-ATPases by REMs represents an evolutionary innovation that predates the origin of the root system itself. This study thus uncovers an ancient alkalinization mechanism co-opted by the root developmental program and infers that pHe patterning may have shaped morphogenesis evolution.

plant biology↗

Cell-type specific gating of gene regulatory modules as a hallmark of early immune responses in Arabidopsis leaves

In plants, many cell types contribute to immunity, but what division of labor exists among cell types when immunity is activated? We compared, at single-cell resolution, the response of Arabidopsis thaliana leaf cells during pattern-triggered and effector-triggered immunity (PTI/ETI), sampled at 3 and 5 hours after infection with Pseudomonas syringae DC3000. Core defense modules were broadly shared across cell clusters, but their activation varied in timing and intensity, with key immune receptors also showing cell type-specific expression dynamics. We identified distinct mesophyll cell populations based on their resilience patterns: after the initial response, some cells continue to express defense genes at high levels during both PTI and ETI, while others quickly reinitiate growth-related gene expression programs, but only during PTI. Gene regulatory network inference revealed WRKY-regulated modules enriched in cells sensing effectors, while SA biosynthesis regulators were activated in complementary clusters. Finally, we used the cue1-6 mutant to demonstrate that core immune responses are robust despite altered leaf architecture. In addition, we uncovered cryptic defense pathways, including sucrose-responsive modules, in this mutant. By capturing early immune responses at high resolution, our study reveals cell type-specific coordination of plant immunity and provides a framework for decoding immune signaling networks.

plant biology↗

TCR-engineered T-cells directed against Ropporin-1 constitute a safe and effective treatment for triple-negative breast cancer in near-clinical models

Triple-negative breast cancer (TNBC) shows an urgent need for new therapies. We discovered Ropporin-1 (ROPN1) as a target to treat TNBC with T-cells. ROPN1 showed high and homogenous expression in 90% of primary and metastatic TNBC but not in healthy tissues. HLA-A2-binding peptides were detected via immunopeptidomics and predictions and used to retrieve T-cell receptors (TCRs) from naive repertoires. Following gene introduction into T-cells and stringent selection, we retrieved a highly specific TCR directed against the epitope FLYTYIAKV that did not recognize non-cognate epitopes from alternative source proteins. Notably, this TCR mediated killing of three-dimensional tumoroids in vitro and tumor cells in vivo and outperformed standard-of-care drugs. Finally, the T-cell product expressing this TCR and manufactured using a clinical protocol fulfilled standard safety and efficacy assays. Collectively, we have identified and preclinically validated ROPN1 as a target and anti-ROPN1 TCR T-cells as a treatment for the vast majority of TNBC patients.

immunology↗

microRNA165 and 166 modulate salt stress response of the Arabidopsis root.

In plants, developmental plasticity allows for the modulation of organ growth in response to environmental cues. Being in contact with soil, roots are the first organ responding to soil abiotic stresses such as high salt concentration. In the root, plasticity relies on changes in the activity of the apical meristem, the region at the tip of the root where a set of self-renewing undifferentiated stem cells sustains growth. We show that salt stress promotes root meristem cells differentiation via reducing the dosage of the microRNAs miR165 and 166. By means of genetic, molecular and computational analysis, we show that the levels of miR165 and 166 respond to high salt concentration, and that miR165 and 166-dependent PHB modulation is fundamental for the response of root growth to this stress. Salt dependent reductions of miR165 and 166 causes rapid increase of the Arabidopsis homeobox protein PHABULOSA (PHB) expression and production of the root meristem pro-differentiation hormone cytokinin. Our data provide direct evidence of how the miRNA-dependent modulation of transcription factors dosage mediates plastic development in plants. In plants, development must be both robust - to ensure appropriate growth - and plastic - to enable the adaptation to external cues. Plastic development largely depends on the modulation of gene expression, controlling the concentration of developmental factors, such as hormones, transcription factors (TFs) and signalling molecules (Garcia-Molina et al, 2013; Hofhuis & Heidstra, 2018; Lopez-Ruiz et al, 2020; Schroder et al, 2021). A classic example of plant developmental plasticity is the adaptation of plant growth to high salt conditions, a stress that inhibits shoot and root development (Flowers et al, 1997). Roots are the first organs sensing salt concentration in soil, where high salt reduces meristem activity and root growth (Dinneny et al, 2008; Geng et al, 2013; Jiang et al, 2016). It has been suggested that the regulation of several plant hormones and miRNAs mediate the plant response to salt stress (Dolata et al, 2016; Geng et al, 2013; Iglesias et al, 2014; Jiang et al, 2016; Nishiyama et al, 2011; Yan et al, 2016). However, the molecular interplays mediating the adaptation of plant roots to salt stress are still vague. Post-embryonic root growth is supported by the activity of the root meristem, a region located at the root tip where self-renewing stem cells divide asymmetrically in the stem cell niche (SCN), originating transit-amplifying daughter cells that divide in the division zone (DZ) (Di Mambro et al, 2018). Once these cells reach a developmental boundary denominated transition zone (TZ), they stop dividing and start to elongate in the so-called elongation/differentiation zone (EDZ) (Di Mambro et al, 2018). A dynamic balance between cell division and cell differentiation ensures continuous root growth, maintaining a fixed number of cells in the DZ. Alterations in this dynamic equilibrium promote or inhibit root growth (Di Mambro et al, 2018; Salvi et al, 2020). microRNA molecules (miRNA) play a key role in the control of root meristem development (Bertolotti et al, 2021a; Skopelitis et al, 2012). Maturation of plant miRNAs depends on the activity of a multiprotein complex comprising the DICER-LIKE1 (DCL1), HYPONASTIC LEAVES1 (HYL1) and SERRATE (SE) proteins that cut pre-miRNA transcripts into 21 nucleotides mature miRNA (Yan et al, 2016). Among miRNAs, miR165 and 166 have been shown to be main regulator of root development (Carlsbecker et al, 2010; Dello Ioio et al, 2012). miR165 and miR166 are pleiotropic regulators of plant developmental processes. miR165 and 166 family consists of nine independent loci (MIR165 A-B and MIR166 A-G) that drive expression of pre-miR165 and 166 in different tissues and at different developmental stages (Miyashima et al, 2011). miR165/166 activity is crucial in the control of robust development, restricting the expression of the HOMEODOMAIN LEUCINE ZIPPER III (HD-ZIPIII), including PHABULOSA (PHB) and PHAVOLUTA (PHV), which are involved in root and shoot development, vascular growth, and leaf and embryo polarity (Carlsbecker et al, 2010; Dello Ioio et al, 2012; Di Ruocco et al, 2017; Grigg et al, 2009; McConnell et al, 2001; Skopelitis et al, 2017; Williams et al, 2005). In the root, miR165/166 regulate meristem homeostasis and radial patterning (Carlsbecker et al, 2010; Dello Ioio et al, 2012); pre-miR165a, pre-miR166a and b transcription is promoted by the SCARECROW (SCR) and SHORTROOT (SHR) transcription factors (Carlsbecker et al, 2010) and, thanks to the cell-to-cell mobility, mature miR165 and 166 forms diffuse to patterns both the root vasculature and the ground tissue (Carlsbecker et al, 2010; Miyashima et al, 2011; Skopelitis et al, 2018; Vaten et al, 2011; Bertolotti et al, 2021b). In the root meristem the miR165-166-PHB module promotes the synthesis of the plant hormone cytokinin, an important player in root developmental plasticity regulating cell differentiation rate of meristematic cells via the activation of the ARABIDOPSIS HISTIDINE KINASE3 (AHK3)/ARABIDOPSIS RESPONSE REGULATOR 1/12 (ARR1/12) pathway (Dello Ioio et al, 2007,2008). Here, we show that in response to salt stress miR165 and 166 modulates PHB expression to adjust root meristem activity. Salt exposure results in changes in cytokinin biosynthesis, which further regulates the miR165/166-PHB module. Hence, in addition to the above-described miRNA activity in controlling root robust development, we provide clear evidence that, in response to environmental cues, miRNAs are crucial also in the control of root plastic development, modulating the dosage of transcription factors.

plant biology↗

Phylogenomics reveals major diversification rate shifts in the evolution of silk moths and relatives

The silkmoths and their relatives (Bombycoidea) are an ecologically and taxonomically diverse superfamily that includes some of the most charismatic species of all the Lepidoptera. Despite displaying some of the most spectacular forms and ecological traits among insects, relatively little attention has been given to understanding their evolution and the drivers of their diversity. We heavily sampled (both in taxa and loci) all major lineages of the Bombycoidea, producing a well-supported phylogeny that identified important evolutionary patterns (e.g., morphology, biogeography, and differences in speciation and extinction). Importantly, analysis of diversification rates highlights the stark increases that exist within the Sphingidae (hawkmoths) and Saturniidae (wild silkmoths). We postulate that these rate shifts are due to differences in the intense selective pressures from insectivorous bats. The study also introduces a new Bombycoidea-specific Anchored Hybrid Enrichment (AHE) probe set, a modified DNA extraction protocol for Lepidoptera specimens from natural history collections, and additional information on the existing AHE bioinformatics pipeline. Our research highlights the flexibility of AHE to generate genomic data from a wide range of museum specimens, both age and preservation method, and will allow researchers to tap into the wealth of biological data residing in natural history collections around the globe.

evolutionary biology↗