Biology subjects

Farley, A.

Publications and source records attributed to Farley, A..

4 recordsLinked to original sources

bioRxiv2026

Sensory experience and mTORC1 interplay orchestrates the maturation of cortical interneuron connectivity and tactile sensitivity

Sensory abnormalities are core features of neurodevelopmental disorders, including autism. Although interneuron dysfunction is hypothesized to contribute to these deficits, the underlying mechanisms remain unclear. Here, we demonstrate that mTORC1 dysregulation in parvalbumin-expressing (PV) interneurons drives heightened tactile exploration and defensiveness. These behavioral changes coincide with whisker-evoked cortical responses characterized by increased power but degraded temporal precision. Excitatory inputs to PV cells, their intrinsic excitability and in vivo firing rate during tactile exploration are reduced, suggesting that mutant PV cells are hypoactive. Whisker trimming restricted to the third postnatal week prevented mTORC1 hyperactivation, PV cell input and output connectivity deficits as well as abnormal tactile cortical responses and behavior in adult mutant mice. Further, this manipulation rescued sociability deficits. Altogether, these data suggest that the interplay between mTORC1 signaling and sensory experience in PV cells regulates their connectivity, and contributes to the proper development of tactile and social behavior.

neuroscience↗

bioRxiv2024

Vascular mural cells protect the adult brain from haemorrhage but do not control the blood-brain barrier in developing zebrafish

The blood-brain barrier (BBB) protects the brain from circulating metabolites and plays central roles in neurological diseases. Endothelial cells (ECs) of the BBB are enwrapped by mural cells including pericytes and vascular smooth muscle cells (vSMCs) that regulate angiogenesis, vessel stability and barrier function. To explore mural cell control of the BBB, we investigated neurovascular phenotypes in zebrafish pdgfrb mutants that lack brain pericytes and vSMCs. As expected, mutants showed an altered cerebrovascular network with mispatterned capillaries. Unexpectedly, mutants displayed no BBB leakage at larval stages of development. This demonstrates that pericytes and vSMCs do not control BBB function in developing zebrafish. Instead, we observed juvenile and adult BBB disruption occurring at "hotspot" focal hemorrhages at large vessel aneurysms. ECs at leakage hotspots showed induction of caveolae on abluminal surfaces and structural defects including basement membrane thickening and disruption. Our work suggests that capillary pericytes regulate cerebrovascular patterning in development and vSMCs of major arteries protect from hemorrhage and BBB breakdown in older zebrafish. The fact that young zebrafish have a functional BBB in the absence of mural cells calls for renewed interrogation of mural cell control of the BBB throughout vertebrate evolution.

developmental biology↗

bioRxiv2024

Clonal analysis of fetal hematopoietic stem/progenitor cell subsets reveals how post-transplantation capabilities are distributed

It has been proposed that adult haematopoiesis is sustained by multipotent progenitor (MPP) clones that are specified during development. From an immunophenotypic perspective, it is known that hematopoietic stem cell (HSC) and MPPs are present in the fetal liver yet our understanding of how fetal MPPs functionally compare to those in the adult bone marrow is incomplete. Using acute-term transplantations, we found that at a population-level fetal immunophenotypic MPP classes exhibited similar lineage biases as adult cells, albeit with some difference in lymphoid output. Clonal assessment of fetal MPPs engraftment revealed that lineage biases largely resulted from differences in the pattern of single-or bi-lineage differentiation. Immunophenotypic long-term (LT)-and short-term (ST)-HSCs in the fetal liver were distinguished from MPPs according to propensity for clonal multi-lineage differentiation. We also discovered that a large cohort of long-term repopulating units (LT-RU) were within the immunophenotypic ST-HSC population, a significant portion of these were labelled using Flt3-cre. This finding has two implications: (1) use of the CD150+ LT-HSC immunophenotype alone will systematically underestimate the size and diversity of the fetal LT-RU pool; and, (2), given fetal LT-RUs with a ST-HSC immunophenotype have the functional attributes required to persist into adulthood.

developmental biology↗

bioRxiv2022

Analysis of organelle content supports a membrane budding model of platelet biogenesis

Understanding how in vivo platelet biogenesis is undertaken is critical to making on-demand platelet production for clinical use feasible. We recently described the discovery of plasma membrane budding as a major in vivo platelet-producing pathway. In vitro recapitulation of this finding could pave the way towards efficient laboratory-based platelet production. The plausibility of the plasma membrane budding model has been called into question. The foundation of this is the contention that the size and payload composition of plasma membrane buds are not consistent with bona fide platelets. Thus, membrane buds likely represent stages in megakaryocyte-derived microparticle formation. Using 3D super-resolution imaging, we have performed a quantitative comparison of size and organelle content of plasma membrane buds, platelets, and microparticles in the adult mouse bone marrow. We unequivocally demonstrate that the structures we previously described as membrane buds exhibit the same size range as free platelets, that all buds contain organelles, and that membrane buds and free platelets contained an equivalent number of organelles. Crucially, membrane buds and microparticles are completely distinct from each other. To prevent future confusion between the processes of microparticle formation and platelet biogenesis, we propose using the more specific term "pre-platelet membrane buds".

cell biology↗