Biology subjects

Sarov, M.

Publications and source records attributed to Sarov, M..

4 recordsLinked to original sources

bioRxiv2023

Primate-expressed EPIREGULIN promotes basal progenitor proliferation in the developing neocortex

Neocortex expansion during evolution is linked to higher numbers of neurons thought to result from increased proliferative capacity and neurogenic potential of basal progenitor cells (BPs) during development. Here we show that EREG, encoding the growth factor EPIREGULIN, is expressed in the human developing neocortex and in gorilla organoids, but not in the mouse neocortex. Addition of EPIREGULIN to the mouse neocortex increases proliferation of BPs via EGFR-mediated signaling, whereas ablation of EREG in human cortical organoids reduces BP proliferation. Addition of EPIREGULIN to cortical organoids promotes a further increase in proliferation of gorilla but not human BPs. Finally, we identify putative cis-regulatory elements that may contribute to inter-species differences in EREG expression. Overall, our results suggest that species-specific expression of EPIREGULIN may contribute to increased neocortex size in primates by providing a pro-proliferative signal to BPs in the subventricular zone progenitor niche.

developmental biology↗

bioRxiv2022

Longer metaphase and fewer chromosome segregation errors in modern human than Neandertal brain development

Since the ancestors of modern humans separated from those of Neandertals, around one hundred amino acid substitutions spread to essentially all modern humans. The biological significance of these changes is largely unknown. Here, we examine all six such amino acid substitutions in the three proteins known to have key roles in kinetochore function and chromosome segregation and to be highly expressed in the stem cells of the developing neocortex. When we introduce these modern human-specific substitutions in the mouse, three substitutions in two of these proteins, KIF18a and KNL1, cause a prolongation of metaphase and a reduction in chromosome segregation errors in apical progenitors of the developing neocortex. Conversely, the ancestral substitutions cause a reduction in metaphase length and an increase in chromosome segregation errors in human brain organoids. Our data also show that, in these aspects, Neandertals were more similar to chimpanzees than to modern humans. Thus, the fidelity of chromosome segregation during neocortex development improved in modern humans after their divergence from Neandertals.

neuroscience↗

bioRxiv2020

Recapitulating evolutionary divergence in a single regulatory element causes expression changes of the lens gene Tdrd7

Mutations in cis-regulatory elements play important roles for phenotypic changes during evolution. Eye degeneration in the blind mole rat (BMR) and other subterranean mammals is significantly associated with widespread divergence of eye regulatory elements, but the effect of these regulatory mutations on eye development and function has not been explored. Here, we investigate the effect of mutations observed in the BMR sequence of a conserved non-coding element upstream of Tdrd7, a pleiotropic gene required for lens development and spermatogenesis. We first show that this conserved element is a transcriptional repressor in lens cells and that the BMR sequence partially lost repressor activity. Next, we recapitulated the evolutionary changes by precisely replacing the endogenous regulatory element in a mouse line by the orthologous BMR sequence with CRISPR-Cas9. Strikingly, this repressor element has a large effect, causing a more than two-fold up-regulation of Tdrd7 in developing lens. Interestingly, the increased mRNA level does not result in a corresponding increase in TDRD7 protein nor an obvious lens phenotype, likely explained by buffering at the posttranscriptional level. Our results are consistent with eye degeneration in subterranean mammals having a polygenic basis where many small-effect mutations in different eye-regulatory elements collectively contribute to phenotypic differences.

evolutionary biology↗

bioRxiv2020

Cooperative molecular networks drive a mammalian cell state transition

In the mammalian embryo, epiblast cells must exit their naive state and acquire formative pluripotency. This cell state transition is recapitulated by mouse embryonic stem cells (ESCs), which undergo pluripotency progression in defined conditions in vitro. However, our understanding of the molecular cascades and gene-networks involved in the exit from naive pluripotency remains fragmented. Here we employed a combination of genetic screens in haploid ESCs, CRISPR/Cas9 gene disruption, large-scale transcriptomics and computational systems-biology to delineate the regulatory circuits governing naive state exit. Transcriptome profiles for 73 knockout ESC lines predominantly manifest delays on the trajectory from naive to formative epiblast. We find that gene networks operative in ESCs are active during transition from pre- to post-implantation epiblast in utero. We identified 374 naive-associated genes tightly connected to epiblast state and largely conserved in human ESCs and primate embryos. Integrated analysis of mutant transcriptomes revealed funneling of multiple gene activities into discrete regulatory modules. Finally, we delineate how intersections with signaling pathways direct this pivotal mammalian cell state transition.

systems biology↗