Biology subjects

Grill, S.

Publications and source records attributed to Grill, S..

6 recordsLinked to original sources

bioRxiv2026

Decoupling Transcription from Cell Fate Preserves Germ Cell Totipotency

Only germ cells can give rise to a totipotent embryo, yet a conserved transcriptional program for germ cell identity remains elusive. Profiling Drosophila primordial germ cells (PGCs) across embryogenesis, we find that nascent PGCs are not silent, as previously thought, but instead transcribe the same totipotency program as the early embryo, reflecting an open chromatin state. This chromatin state, established by the pioneer factor Zelda, persists in PGCs throughout development. The associated transcriptional program normally drives somatic differentiation, but in PGCs the conserved RNA-regulator Nanos represses its translation, leaving germline chromatin uncommitted. Cells that fail to establish the totipotent state die before reaching the gonad. Thus, germ cells preserve developmental potential not by restricting transcription, but by preventing transcripts from determining cell fate.

developmental biology↗

bioRxiv2023

DJ-1 products glycolic acid and D-lactate restore deficient axonal trafficking and DNA damage response in FUS and SOD1-associated amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disease leading to death within 2-5 years. Currently available drugs can only slightly prolong survival. Despite the progress that has been achieved in unravelling the molecular mechanisms of the disease so far, the underlying pathophysiology is not fully understood. We present novel insights into the pathophysiology of Superoxide Dismutase 1 (SOD1)- and in particular Fused In Sarcoma (FUS)-ALS by revealing a putatively central role of the Parkinsons disease (PD) associated glyoxylase DJ-1 and its products glycolic acid (GA) and D-lactic acid (DL). Combined, but not single, treatment with GA and DL restored axonal trafficking deficits of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was accompanied by restoration of mitochondrial membrane potential as well as mitochondrial fragmentation (FUS-ALS) or elongation (SOD1-ALS). Furthermore, GA and DL restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites. We further show that despite presenting an early axonal transport deficiency as well, TDP-43 patient-derived MNs did not share this mechanism. While this points towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different gene variants of ALS. Thus, we introduce a putative novel treatment for ALS based on a combination of the two substances GA and DL which might be not only an interesting novel drug candidate in subsets of ALS cases but also in other neurodegenerative diseases characterized by mitochondrial depolarization.

neuroscience↗

bioRxiv2023

Young gene HP6/Umbrea is dispensable for viability and fertility

Studies of the young gene Heterochromatin Protein 6 (HP6) have challenged the dogma that essential functions are only seen in genes with a long evolutionary history. Based on its prominent expression in Drosophila germ cells, we asked if HP6 might play a role in germline development. Surprisingly, we found that CRISPR-generated HP6 null mutants are viable and fertile. We identified an independent lethal allele and an RNAi off-target effect that prevented accurate interpretation of HP6 essentiality in previous studies. We found that the vast majority of young essential genes were viable when tested with orthologous methods. Together our data call into question the frequency with which young genes gain essential functions.

evolutionary biology↗

bioRxiv2023

Reinforcement-Based Processes Actively Regulate MotorExploration Along Redundant Solution Manifolds

From a babys babbling to a songbird practicing a new tune, exploration is critical to motor learning. A hallmark of exploration is the emergence of random walk behaviour along solution manifolds, where successive motor actions are not independent but rather become serially dependent. Such exploratory random walk behaviour is ubiquitous across species, neural firing, gait patterns, and reaching behaviour. Past work has suggested that exploratory random walk behaviour arises from an accumulation of movement variability and a lack of error-based corrections. Here we test a fundamentally different idea--that reinforcement-based processes regulate random walk behaviour to promote continual motor exploration to maximize success. Across three human reaching experiments we manipulated the size of both the visually displayed target and an unseen reward zone, as well as the probability of reinforcement feedback. Our empirical and modelling results parsimoniously support the notion that exploratory random walk behaviour emerges by utilizing knowledge of movement variability to update intended reach aim towards recently reinforced motor actions. This mechanism leads to active and continuous exploration of the solution manifold, currently thought by prominent theories to arise passively. The ability to continually explore muscle, joint, and task redundant solution manifolds is beneficial while acting in uncertain environments, during motor development, or when recovering from a neurological disorder to discover and learn new motor actions.

neuroscience↗

bioRxiv2021

Habitat deterioration despite protection: long-term declines of littoral area of fishponds in Czech nature reserves

Fishponds play a key role in current pondscapes in many developed countries. Their littoral areas, supporting multiple ecosystem functions including the maintenance of aquatic and riparian biodiversity, have been adversely affected by the move shift towards more intensive aquaculture and widespread eutrophication in the middle 20th century. To counteract these changes, many fishponds received some protection, but its long-term efficiency has not been studied. Here we focus on the role of conservation status in protecting the area of littoral areas of fishponds in Czechia between the years 1950 and 2019. We found that the conservation status of these fishponds did not prevent habitat deterioration in most of the fishponds, especially during the second half of the 20th century. Moreover, we detected no significant effects of the reserve establishment year, fishpond area and conservation target on the littoral areas. This suggests that the conservation measures are insufficient across fishpond reserve types. We attribute the negative trends to persisting high fish stocks, especially of common carp, and eutrophication resulting from additional feeding, pond manuring, and ongoing nutrient inputs from the pond catchments. Sediment dredging and high grazing pressure by waterfowl in some reserves can further aggravate the situation. We conclude that effective protection of the littoral areas requires a paradigm shift towards less intensive fish stock management, more frequent summer drainage, and effective reduction of all nutrient inputs to increase the water quality. Such measures can help recover the littoral areas and the associated biota. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=54 SRC="FIGDIR/small/473897v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@8e9b31org.highwire.dtl.DTLVardef@6ecaf9org.highwire.dtl.DTLVardef@1cfaefdorg.highwire.dtl.DTLVardef@1e9952f_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LILittoral vegetation in ponds supports high biodiversity but often lacks protection. C_LIO_LIWe evaluated long-term changes in the littoral areas of fishponds in Czechia. C_LIO_LIThe areas decreased markedly in both protected and unprotected ponds since 1950. C_LIO_LIReserve duration, fishpond area and conservation target did not affect the trends. C_LIO_LIChanges in fishpond management are recommended for littoral area recovery. C_LI

ecology↗

bioRxiv2019

Two separation-of-function isoforms of human TPP1 and a novel intragenic noncoding RNA dictate telomerase regulation in somatic and germ cells.

Telomerase replicates chromosome ends in germ and somatic stem cells to facilitate continued proliferation. Telomerase action depends on the telomeric protein TPP1, which recruits telomerase to telomeres and facilitates processive DNA synthesis. Here we identify separation-of-function long (TPP1-L) and short (TPP1-S) isoforms of TPP1 differing only in 86 amino acids at their N-terminus. While both isoforms retain the ability to recruit telomerase, only TPP1-S facilitates telomere synthesis. We identify a novel intragenic noncoding RNA in the 3-UTR of the TPP1-encoding gene that specifically shuts down telomerase activation-incompatible TPP1-L to establish TPP1-S as the predominant isoform in somatic cells. Strikingly, TPP1-L is the major isoform in testes, where it can function to restrain telomerase in mature germ cells. Our studies uncover how differential expression of two isoforms allows TPP1 to perform separate functions in different cells, and demonstrate how isoform choice can be determined by an intragenic noncoding RNA.

biochemistry↗