Reyes, C. M. | bioRxiv Science

bioRxiv2026

FMR1 reduction alters cellular and circuit properties in human cortex

Transcriptional silencing of FMR1 results in Fragile X syndrome (FXS), the leading inherited cause of intellectual disability (ID) and autism. The Fmr1-/y mouse model has been used to identify FXS disease mechanisms, whereas mechanistic insights from human brain are lacking. By leveraging organotypic human cortical slices and viral tools to reduce FMR1 expression, we create a new model that captures cell type-specific transcriptomic changes similar to FXS patient cortex that are not seen in the Fmr1-/y mouse. Among these are ion channel subunit changes in deep layer pyramidal neurons, which are consistent with a robust hyperexcitability seen by whole-cell patch-clamp recordings, and increased synchronized activity revealed by 2-photon calcium imaging. Together, this work defines the impact of FMR1 reduction in human cortex and provides a new model for testing therapeutic interventions in FXS.

neuroscience↗

bioRxiv2025

How infant brains fold: Sulcal deepening is linked to development of sulcal span, thickness, curvature, and microstructure

Cortical folding begins in utero as sulci emerge and continues postnatally as sulci deepen. However, the timeline and mechanisms underlying postnatal sulcal development remain unknown. Using structural and quantitative magnetic resonance imaging in infants from birth to one year of age, we longitudinally measured macroanatomical and microstructural development in major sulci that emerge in utero between the 16th and 31st gestational weeks. We find that sulci that emerge earlier in utero are deeper at birth and deepen at a slower rate postnatally than later emerging sulci. Sulci also become wider, thicker, and microstructurally denser, while their curvature decreases. Notably, mean sulcal depth is predicted by a weighted sum of sulcal span, thickness, curvature, and tissue microstructure, with differential weights across sulci. Analysis of local depth along the sulcus also reveals that deeper portions of sulci (fundi) have higher curvature and higher microstructural density than the surrounding sulcal walls. These data reveal that postnatal sulcal deepening is nonuniform and depends on the time of emergence in utero, tissue microstructure, and multiple macroanatomical factors. Together, these findings have important ramifications for theories of cortical folding and elucidating neurodevelopmental disorders and delays.

neuroscience↗

bioRxiv2020

Spontaneous replication fork collapse regulates telomere length homeostasis in wild type cells

In most eukaryotes, the enzyme telomerase maintains the termini of linear chromosomes through the addition of repetitive telomeric sequences. It is widely assumed that the primary site of action for telomerase is the single-stranded G-rich overhang at the ends of linear chromosomes. We show here that a second substrate, created by spontaneous replication fork collapse during duplex telomeric DNA replication in wild type budding yeast, is elongated by telomerase at a much higher frequency ([~]50%) than fully replicated chromosome termini. Furthermore, as much as [~]200 nucleotides can be added in a single cell division to these newly collapsed forks, indicating that spontaneous replication fork collapse and the subsequent response by telomerase is a major determinant of telomere length homeostasis. This challenges a long-standing model for telomere length regulation which posits a length-sensing mechanism that assesses individual telomeres to determine whether chromosome ends are in "telomerase-extendible" or "telomerase-non-extendible" states. We propose that these two states are instead structurally and temporally distinct substrates for telomerase, generated by two different processes (fork collapse vs. completion of DNA replication). We also show that replication fork collapse at telomeres is kept in check by a telomere-dedicated Cdc13/Stn1/Ten1 complex in collaboration with the canonical RPA complex, indicating that these two complexes bind single-stranded DNA exposed at the replication fork to facilitate replisome progression through duplex telomeric DNA. Although failures during DNA replication are often genotoxic events, this represents an opposing example in which fork collapse has been co-opted to promote genome stability. Significance StatementIn most eukaryotes, the termini of linear chromosomes are composed of arrays of short repeats that are continually replenished by the enzyme telomerase. If telomerase is unable to act, gradual loss of these terminal repeats results in an eventual block to cell division. Therefore, in cells that depend on continuous cell division, the mechanism(s) by which telomerase is directed to chromosome ends is tightly regulated. This study shows that in addition to the ends of fully replicated chromosomes, a second site of action for telomerase is generated when replication through duplex telomeric DNA is disrupted. These results suggest that the disparate response of telomerase to two temporally and structurally distinct substrates is a major determinant of telomere length homeostasis.

genetics↗