Species-specific developmental timing is associated with global differences in protein stability in mouse and human

Abstract

11What determines the pace of embryonic development? Although many molecular mechanisms controlling 12 developmental processes are evolutionarily conserved, the speed at which these operate can vary substantially 13 between species. For example, the same genetic programme, comprising sequential changes in transcriptional 14 states, governs the differentiation of motor neurons in mouse and human, but the tempo at which it operates differs 15 between species. Using in vitro directed differentiation of embryonic stem cells to motor neurons, we show that the 16 programme runs twice as fast in mouse as in human. We provide evidence that this is neither due to differences in 17 signalling, nor the genomic sequence of genes or their regulatory elements. Instead, we find an approximately two-18 fold increase in protein stability and cell cycle duration in human cells compared to mouse. This can account for the 19 slower pace of human development, indicating that global differences in key kinetic parameters play a major role in 20 interspecies differences in developmental tempo. 22 24Although the order and underlying molecular mechanisms are often indistinguishable between different species, the 25 pace at which they progress can differ substantially. For example, compared to their rodent counterparts, neural 26 progenitors in the primate cortex progress more slowly through a temporal sequence of neuronal subtype 27 production (3). Moreover, in different species of primates, the duration of progenitor expansion differs, which at 28 least partly accounts for differences in brain size (4, 5). Even in more evolutionary conserved regions of the central 29 nervous system (CNS) there are differences in tempo. The specification of neuronal subtype identity in the vertebrate 30 spinal cord involves a conserved and well-defined gene regulatory programme comprising a series of changes in 31 transcriptional state as cells acquire specific identities and differentiate from neural progenitors to post-mitotic 32 neurons (6). The pace of this process differs between species, despite the similarity in the regulatory programme 33 and the structural and functional correspondence of the resulting spinal cords. For example, the differentiation of 34 motor neurons (MNs), a prominent neuronal subtype of the spinal cord, takes less than a day in zebrafish, 3-4 days 35 in mouse, but in humans it takes ~2 weeks (7, 8). Moreover, differences in developmental tempo are not confined 36 to the CNS. The oscillatory gene expression that regulates the sequential formation of vertebrate body segments -37 the segmentation clock -has a period that ranges from ~30mins in zebrafish, to 2-3h in mouse, and 5-6h in human 38 (9)(10)(11). What causes this developmental allochrony -interspecies differences in developmental tempo -is unclear. 39To address this question, we set out to compare the generation of mouse and human MNs in the developing spinal 40 cord. Progenitors of the spinal cord arise from the caudal lateral epiblast in the posterior of the elongating...

Species-specific developmental timing dictates expansion of the avian wing skeletal pattern

“…It is The copyright holder for this preprint this version posted March 22, 2021. ; https://doi.org/10.1101/2021.03.22.436457 doi: bioRxiv preprint 15 degradation rates in determining the timing of proximo-distal specification. In a similar manner, the rate of protein degradation in cultured mouse cells is approximately twice as fast as is found in human cells, which correlates with the tempo of somitogenesis and motor neuron differentiation (40,41) . It remains to be determined if altering the degradation of specific signalling molecules and/or proteins is sufficient to switch human and mouse developmental timing, and if this has implications for in vivo tissue scaling.…”

Single cell transcriptomics identifies master regulators of neurodegeneration in SOD1 ALS motor neurons

“…This led us to question whether ALS MN displayed aberrant activation of signalling pathways that are active during development. To test this hypothesis, we obtained gene expression profiling data over the time course of motor neuron differentiation from neuromesodermal progenitors (D0) to motor neurons (D15) (GSE140747)[22]. We used DESeq2 to generate a list of genes differentially expressed between D0 neuromesodermal progenitors (NMP) and D15 neurons.…”

“…We obtained both, the full (all genes) and the filtered (PC1 adjusted genes) datasets. Count data for GSE140747[22] (motor neuron development gene expression: D0-D15) and GSE98288[23, 24] (D21, D35 vs iPSC) was downloaded from the gene expression omnibus. For GSE98288, we only used counts from the control iPSC differentiations.…”

Genetic Developmental Timing Revealed by Inter-Species Transplantations in Fish

“…Our experiments add to the growing evidence on autonomous organisation of biological systems [2,49,50] with a focus on developmental dynamics. It has recently been suggested that in mammals, developmental timing depends on protein stability, a kinetic parameter that has species-specific features [51]. Whether the same holds true for an entire extrinsic organ developing in a different host species is an attractive hypothesis that needs to be formally tested.…”