Biology subjects

Christensen, M. M.

Publications and source records attributed to Christensen, M. M..

5 recordsLinked to original sources

bioRxiv2023

Conserved and derived expression patterns and positive selection on dental genes reveal complex evolutionary context of ever-growing rodent molars

Continuously growing teeth are an important innovation in mammalian evolution, yet genetic regulation of continuous growth by stem cells remains incompletely understood. Dental stem cells responsible for tooth crown growth are lost at the onset of tooth root formation. Genetic signaling that initiates this loss is difficult to study with the ever-growing incisor and rooted molars of mice, the most common mammalian dental model species, because signals for root formation overlap with signals that pattern tooth size and shape (i.e., cusp patterns). Different species of voles (Cricetidae, Rodentia, Glires) have evolved rooted and unrooted molars that have similar size and shape, providing alternative models for studying roots. We assembled a de novo genome of Myodes glareolus, a vole with high-crowned, rooted molars, and performed genomic and transcriptomic analyses in a broad phylogenetic context of Glires (rodents and lagomorphs) to assess differential selection and evolution in tooth forming genes. We identified 15 dental genes with changing synteny relationships and six dental genes undergoing positive selection across Glires, two of which were undergoing positive selection in species with unrooted molars, Dspp and Aqp1. Decreased expression of both genes in prairie voles with unrooted molars compared to bank voles supports the presence of positive selection and may underlie differences in root formation. Bulk transcriptomics analyses of embryonic molar development in bank voles also demonstrated conserved patterns of dental gene expression compared to mice, with species-specific variation likely related to developmental timing and morphological differences between mouse and vole molars. Our results support ongoing evolution of dental genes across Glires, revealing the complex evolutionary background of convergent evolution for ever-growing molars.

evolutionary biology↗

bioRxiv2023

On growth and form of the mammary gland: Epithelial-mesenchymal interactions in embryonic mammary gland development

Mammary gland is a unique organ that undergoes dynamic alterations throughout a females reproductive life, making it an ideal model for developmental, stem cell and cancer biology research. Mammary gland development begins in utero and proceeds via a quiescent bud stage before the initial outgrowth and subsequent branching morphogenesis. How mammary epithelial cells transit from quiescence to an actively proliferating and branching tissue during embryogenesis and, importantly, how the branch pattern is determined remain largely unknown. Here we provide evidence indicating that epithelial cell proliferation, segregation into basal and luminal lineages that characterize the postnatal mammary duct, and onset of branching are independent processes, yet partially coordinated by the Eda signaling pathway. By performing heterotypic and heterochronic epithelial-mesenchymal recombination experiments between mammary and salivary gland tissues and ex vivo live imaging, we demonstrate that unlike previously concluded, the mode of branching is an intrinsic property of the mammary epithelium while the growth pace and density of the mammary ductal tree are governed by the mesenchyme. Transcriptomic profiling and ex vivo and in vivo functional studies disclose that mesenchymal Wnt/{beta}-catenin signaling, and in particular IGF-1 downstream of it critically regulate mammary gland growth. These results underscore the general need to carefully decompose the different developmental processes producing branched organs.

developmental biology↗

bioRxiv2022

The developmental basis for scaling of mammalian tooth size

When evolution leads to differences in body size, organs generally scale along. A well-known example of the tight relationship between organ and body size is the scaling of mammalian molar teeth. To investigate how teeth scale during development and evolution, we compared molar development in mouse and rat from initiation through final size. Whereas the linear dimensions of the rat first lower molar are twice that of the mouse molar, their shapes are largely the same. We found that scaling of the molars starts early, and that the rat molar is patterned equally as fast but in a larger size than the mouse molar. Using transcriptomics, we discovered that a known regulator of body size, insulin-like growth factor 1 (Igf1), is more highly expressed in the rat molars compared to the mouse molars. Ex vivo and in vivo mouse models demonstrated that modulation of the IGF pathway reproduces several aspects of the observed scaling process. Furthermore, analysis of IGF1-treated mouse molars and computational modeling indicate that IGF signaling scales teeth by simultaneously enhancing growth and by inhibiting the cusp patterning program, thereby providing a relatively simple mechanism for scaling teeth during development and evolution. Finally, comparative data from shrews to elephants suggest that this scaling mechanism regulates the minimum tooth size possible, as well as the patterning potential of large teeth.

developmental biology↗

bioRxiv2022

GECT - Gene Expression Detection in Developing Tissue Using Micro CT Imaging

High resolution and noninvasiveness have made soft tissue X-ray microtomography ({micro}CT) a widely applicable three-dimensional (3D) imaging method in studies of morphology and development. However, scarcity of molecular probes to visualize gene activity with {micro}CT has remained a challenge. Here we apply horseradish peroxidase -assisted reduction of silver and catalytic gold enhancement of the silver deposit to in situ hybridization in order to detect gene expression in developing tissues with {micro}CT (here called GECT, Gene Expression CT). We show that GECT detects expression patterns of collagen type II alpha 1 (Col2a1) and sonic hedgehog (Shh) in developing mouse tissues comparably with an alkaline phosphatase-based detection method. After detection, expression patterns are visualized with laboratory {micro}CT, demonstrating that GECT is compatible with varying levels of gene expression and varying sizes of expression regions. Additionally, we show that the method is compatible with prior phosphotungstic acid (PTA) staining, a conventional contrast staining approach in {micro}CT imaging of soft tissues. Overall, GECT is a method that can be integrated with existing laboratory routines to obtain spatially accurate 3D detection of gene expression.

developmental biology↗

bioRxiv2020

DELocal: Chromosomal neighbourhoods having genes of diverse functions allow improved identification of differentially expressed genes

Although most genes share their chromosomal neighbourhood with other genes, distribution of genes has not been explored in the context of individual organ development; the common focus of developmental biology studies. Because developmental processes are often associated with initially subtle changes in gene expression, here we explored whether neighbouring genes are informative in the identification of differentially expressed genes. First, we quantified the chromosomal neighbourhood patterns of genes having related functional roles in the mammalian genome. Although the majority of protein coding genes have at least five neighbours within 1 Mb window around each gene, very few of these neighbours regulate development of the same organ. Analyses of transcriptomes of developing mouse molar teeth revealed that whereas expression of genes regulating tooth development changes, their neighbouring genes show no marked changes, irrespective of their level of expression. Finally, we test whether inclusion of gene neighbourhood in the analyses of differential expression could provide additional benefits. For the analyses, we developed an algorithm, called DELocal that identifies differentially expressed genes by comparing their expression changes to changes in adjacent genes in their chromosomal regions. Our results show that DELocal removes detection bias towards large changes in expression, thereby allowing identification of even subtle changes in development. Future studies, including the detection of differential expression, may benefit from, and further characterize the significance of gene-gene neighbour relationships. Author SummaryDevelopment of organs is typically associated with small and hard to detect changes in gene expression. Here we examined how often genes regulating specific organs are neighbours to each other in the genome, and whether this gene neighbourhood helps in the detection of changes in gene expression. We found that genes regulating individual organ development are very rarely close to each other in the mouse and human genomes. We built an algorithm, called DELocal, to detect changes in gene expression that incorporates information about neighbouring genes. Using transcriptomes of developing mouse molar teeth containing gene expression profiles of thousands of genes, we show how genes regulating tooth development are ranked high by DELocal even if their expression level changes are subtle. We propose that developmental biology studies can benefit from gene neighbourhood analyses in the detection of differential expression and identification of organ specific genes.

bioinformatics↗