Biology subjects

Risgaard, R.

Publications and source records attributed to Risgaard, R..

3 recordsLinked to original sources

bioRxiv2023

Multimodal analysis of neuronal maturation in the developing primate prefrontal cortex

The prefrontal cortex (PFC) is critical for myriad high-cognitive functions and is associated with several neuropsychiatric disorders. Here, using Patch-seq and single-nucleus multiomic analyses, we identified genes and regulatory networks governing the maturation of distinct neuronal populations in the PFC of rhesus macaque. We discovered that specific electrophysiological properties exhibited distinct maturational kinetics and identified key genes underlying these properties. We unveiled that RAPGEF4 is important for the maturation of resting membrane potential and inward sodium current in both macaque and human. We demonstrated that knockdown of CHD8, a high-confidence autism risk gene, in human and macaque organotypic slices led to impaired maturation, via downregulation of key genes, including RAPGEF4. Restoring the expression of RAPGEF4 rescued the proper electrophysiological maturation of CHD8-deficient neurons. Our study revealed regulators of neuronal maturation during a critical period of PFC development in primates and implicated such regulators in molecular processes underlying autism.

neuroscience↗

bioRxiv2023

Age-maintained human neurons demonstrate a developmental loss of intrinsic neurite growth ability

Injury to adult mammalian central nervous system (CNS) axons results in limited regeneration. Rodent studies have revealed a developmental switch in CNS axon regenerative ability, yet whether this is conserved in humans is unknown. Using human fibroblasts from 8 gestational-weeks to 72 years-old, we performed direct reprogramming to transdifferentiate fibroblasts into induced neurons (Fib-iNs), avoiding pluripotency which restores cells to an embryonic state. We found that early gestational Fib-iNs grew longer neurites than all other ages, mirroring the developmental switch in regenerative ability in rodents. RNA-sequencing and screening revealed ARID1A as a developmentally-regulated modifier of neurite growth in human neurons. These data suggest that age-specific epigenetic changes may drive the intrinsic loss of neurite growth ability in human CNS neurons during development. One-Sentence Summary: Directly-reprogrammed human neurons demonstrate a developmental decrease in neurite growth ability.

neuroscience↗

bioRxiv2022

Brain and Organoid Manifold Alignment (BOMA), a machine learning framework for comparative gene expression analysis across brains and organoids

Organoids have become valuable models for understanding cellular and molecular mechanisms in human development including brains. However, whether developmental gene expression programs are preserved between human organoids and brains, especially in specific cell types, remains unclear. Importantly, there is a lack of effective computational approaches for comparative data analyses between organoids and developing humans. To address this, by considering the public data availability and research significance, we developed a machine learning framework, Brain and Organoid Manifold Alignment (BOMA) for comparative gene expression analysis of brains and organoids, to identify conserved and specific developmental trajectories as well as developmentally expressed genes and functions, especially at cellular resolution. BOMA first performs a global alignment and then uses manifold learning to locally refine the alignment, revealing conserved developmental trajectories between brains and organoids. Using BOMA, we found that human cortical organoids better align with certain brain cortical regions than other non-cortical regions, implying organoid-preserved developmental gene expression programs specific to brain regions. Additionally, our alignment of non-human primate and human brains reveals highly conserved gene expression around birth. Also, we integrated and analyzed developmental scRNA-seq data of human brains and organoids, showing conserved and specific cell trajectories and clusters. Further identification of expressed genes of such clusters and enrichment analyses reveal brain- or organoid-specific developmental functions and pathways. Finally, we experimentally validated important specific expressed genes using immunofluorescence. BOMA is open-source available as a web tool for general community use.

bioinformatics↗