Biology subjects

Moustakas-Verho, J. E.

Publications and source records attributed to Moustakas-Verho, J. E..

6 recordsLinked to original sources

bioRxiv2024

Rewinding the developmental tape shows how bears break a developmental rule

Mammals have evolved a broad variety of dental morphologies. Nevertheless, the development of the mammalian dentition is considered highly conserved. Molar size proportions exemplify this as a system where small changes in shared developmental mechanisms yield a defined range of morphological outcomes. The Inhibitory Cascade (IC) model states that as molars develop in a sequence, the first developing anterior molars inhibit the development of subsequent posterior ones. The IC model thus predicts a trend of linear tooth size change along the molar row, as has been observed in a wide range of mammalian taxa with otherwise differing dental morphology. Perhaps the starkest exceptions to the IC rule are bears, in which the second molar is the largest and the third molar is disproportionally small. Here we sought to illuminate when and how during development the bear dentition falls of the IC prediction. We examined molar proportions in seven bear species. The results indicate that development of bear molars deviates from IC expectation already during patterning. Yet, during the earlier cap stage, size proportions of bear molars still seem to adhere to the IC model predictions. Overall, these analyses are suggestive that irrespective of the final outcome, the process of initial splitting of the molar-forming region into individual teeth is conserved and follows the IC rule.

evolutionary biology↗

bioRxiv2022

Foxi3 Suppresses Signaling Center Fate and is Necessary for the Early Development of Mouse Teeth

Tooth morphogenesis is regulated by ectodermal-mesenchymal interactions which are controlled by reiteratively used, evolutionarily conserved pathways. How these signals translate into different cellular behaviors is beginning to be understood. Embryonic cell behaviors are regulated by signaling centers that define organ position, size, and shape. The recently identified initiation knots (IKs) and the well-known enamel knots (EK) are tooth epithelial signaling centers that drive proliferation of the neighboring cells and are involved at different stages of morphogenesis, from the early epithelial thickening to the final formation of shape. Signaling center cell fate and maintenance can be regulated by numerous factors. Here, we studied the early stages of murine incisor and molar epithelial morphogenesis and overcame the previous shortage of early-stage mutant models to functionally manipulate the initiation processes of tooth morphogenesis. We achieved the early conditional knock down of the forkhead-box transcription factor Foxi3 during tooth initiation and used imaging approaches to explore cellular and molecular disease mechanisms, specifically those related to signaling center dysfunction in tooth dysplasia. We show that early deficiency of Foxi3 in incisors and molars frequently arrests growth at bud stage, whereas later knockdown of Foxi3 affects tooth downgrowth and shape. Cell-level analyses revealed a decrease in epithelial proliferation and the ectopic appearance of cells with hallmarks of signaling centers: quiescent cell state and canonical Wnt activity. However, the distribution of these cells was wider all over the tooth buds with abnormal decrease of apoptosis. We postulate that, depending on Foxi3 expression levels, the bud cells shift commitment into signaling center fate, ultimately leading to growth arrest or growth/shape changes, implicating Foxi3 as a regulator of cell fates between the signaling centers and proliferating bud cells.

developmental biology↗

bioRxiv2021

Strong regulatory effects of vgll3 genotype on reproductive axis gene expression in immature male Atlantic salmon

Age at maturity is a major contributor to the diversity of life history strategies in organisms. The process of maturation is influenced by both genetics and the environment, and includes changes in levels of sex hormones and behavior, but the specific factors leading to variation in maturation timing are not well understood. gnrh1 regulates the transcription of gonadotropin genes at the onset of puberty in many species, but this gene is lacking in certain teleost species including Atlantic salmon (Salmo salar), which raises the possibility of the involvement of other important regulatory factors during this process. Earlier research has reported a strong association of alternative alleles of the vgll3 gene with maturation timing in Atlantic salmon, suggesting it as a potential candidate regulating reproductive axis genes. Here, we investigated the expression of reproductive axis genes in immature Atlantic salmon males with different vgll3 genotypes during the spawning period. We detected strong vgll3 genotype-dependent differential expression of reproductive axis genes (such as fshb, lhb, amh and igf3) tested in the pituitary, and testis of one-year-old immature male Atlantic salmon. In addition, we observed differential expression of jun (ap1) and nr5a1b (sf1), potential upstream regulators of gonadotropins in the pituitary, as well as axin2, id3, insl3, itch, ptgs2a and ptger4b, the downstream targets of amh and igf3 in the testis. Hereby, we provide evidence of strong vgll3 genotype-dependent transcriptional regulation of reproductive axis genes prior to sexual maturation together with models for distinct actions of vgll3 genotypes on the molecular processes controlling spermatogenesis in Atlantic salmon.

physiology↗

bioRxiv2020

The initiation knot is a signaling center required for molar tooth development

Signaling centers, or organizers, regulate many aspects of embryonic morphogenesis. In the mammalian molar tooth, reiterative signaling in specialized centers called enamel knots (EKs) determine tooth patterning. Preceding the first, primary EK, a transient epithelial thickening appears whose significance remains debated. Here, using tissue confocal fluorescence imaging with laser ablation experiments, we show that this transient thickening is an earlier signaling center, the molar initiation knot (IK) that is required for the progression of tooth development. IK cell dynamics manifest the hallmarks of a signaling center; cell cycle exit, condensation, and eventual silencing through apoptosis. IK initiation and maturation are defined by the juxtaposition of high Wnt activity cells to Shh-expressing non-proliferating cells, the combination of which drives the growth of the tooth bud, leading to the formation of the primary EK as an independent cell cluster. Overall, the whole development of the tooth, from initiation to patterning, is driven by the iterative use of signaling centers.

cell biology↗

bioRxiv2019

Large single-locus effects for maturation timing are mediated via condition variation in Atlantic salmon

Maturation timing is a pivotal life-history trait balancing probabilities between mortality and reproduction. Environmental vs. genetic contributions to traits associated with maturation initiation, such as growth and body condition, remain uncertain because of difficulties in determining causality. In Atlantic salmon, maturation timing associates with a large-effect locus around vgll3, but how this locus affects maturation remains unknown. We combined controlled breeding with common-garden experimentation at two temperatures and show that vgll3 effects on maturation of males express primarily via body condition, which we demonstrate in the males non-maturing female relatives, thus avoiding reverse causality. Between homozygous vgll3 genotypes, maturation probability differed several folds and female condition differed 2% in both temperature environments. Vgll3 effects explained 25 and 16% of maturation probability heritability and 15 and 6% of female condition heritability, in the warm and cold environment, respectively. Non-significant vgll3 effects on female length were antagonistic to those on condition but of equal proportional size. When controlling for vgll3 effects, genetic correlations changed antagonistically between both maturation and condition vs. growth, suggesting vgll3 as a resource-allocation locus. The results support large vgll3 maturation effects being mediated via environmentally stable body condition effects, enabling rapid co-evolution between the life-history traits.

evolutionary biology↗

bioRxiv2019

Regulatory divergence in vgll3 underlies variation in age at maturity in male Atlantic salmon

A major goal in biology is to understand how evolution shapes variation in individual life histories. Genome-wide association studies have been successful in uncovering genome regions linked with traits underlying life history variation in a range of species. However, lack of functional studies of the discovered genotype-phenotype associations severely restrains our understanding how alternative life history traits evolved and are mediated at the molecular level. Here, we report a cis-regulatory mechanism whereby expression of alternative isoforms of the transcription co-factor vestigial-like 3 (vgll3) associate with variation in a key life history trait, age at maturity, in Atlantic salmon (Salmo salar). Using a common-garden experiment, we first show that vgll3 genotype associates with puberty timing in one-year-old salmon males. By way of temporal sampling of vgll3 expression in ten tissues across the first year of salmon development, we identify a pubertal transition in vgll3 expression where maturation coincided with a 66% reduction in testicular vgll3 expression. The late maturation allele was not only associated with a tendency to delay puberty, but also with expression of a rare transcript isoform of vgll3 pre-puberty. By comparing absolute vgll3 mRNA copies in heterozygotes we show that the expression difference between the early and late maturity alleles is largely cis-regulatory. We propose a model whereby expression of a rare isoform from the late allele shifts the liability of its carriers towards delaying puberty. These results reveal how regulatory differences can be a central mechanism for the evolution of life history traits. Author summaryAlternative life history strategies are an important source of diversity within populations and promote the maintenance of adaptive capacity and population resilience. However, in many cases the molecular basis of different life history strategies remains elusive. Age at maturity is a key adaptive life history trait in Atlantic salmon and has a relatively simple genetic basis. Using salmon age at maturity as a model, we report a mechanism whereby different transcript isoforms of the key age at maturity gene, vestigial-like 3 (vgll3), associate with variation in the timing of male puberty. Our results show how gene regulatory differences in conjunction with variation in gene transcript structure can encode for complex alternative life histories.

evolutionary biology↗