Abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a common form of hereditary stroke with angiopathy and vascular dementia, and mostly caused by missense mutations causing abnormal number of Cys residues in the NOTCH3 gene. CADASIL transgenic mice exhibit late-onset angiopathy phenotypes such as degeneration of vascular smooth muscle cells, deposition of granular osmiophilic material (GOM), and accumulation of extracellular domains of NOTCH3 (NOTCH3ECD). However, the study of pathogenic mechanisms and potential therapeutic approaches are still lacking. In this study, we used the Drosophila AxM1 mutants that also carry a Cys mutation in the Notch extracellular domain as a novel model for studying CADASIL syndrome. We found a defect in tracheal branching, NotchECD accumulation, and GOM formation in AxM1 mutants, mimicking the pathology identified in CADASIL. We have used this system to screen FDA-approved drugs and identified several of them are effective in rescuing tracheal branches and suppressing NotchECD accumulation. These effective drugs also indicate a common pathway toward a possible therapeutic approach toward CADASIL.

 

 

Abstract: Introns in the human genome display a bimodal length distribution, with a prominent class of short introns (≤100 nt). Their compact size imposes spatial constraints on spliceosome assembly, yet their functional significance remains poorly defined. Here, we comprehensively characterized the functional, evolutionary, and mechanistic features of human short introns.
Genes harboring short introns are enriched in essential protein-coding genes and exhibit elevated RNA expression, extended transcript half-lives, and consistently efficient splicing across tissues. Despite the established aging-associated transcriptome instability, short introns are less susceptible to age-related increases in splicing errors, indicating resilience within physiological regulatory perturbations.
Given these robust features, we investigated their evolutionary conservation. Comparative analyses across vertebrates revealed that splice junctions associated with short introns are deeply preserved, traceable to fish lineages. However, short introns have undergone lineage-specific compositional remodeling, with GC-rich short introns selectively expanded and associated with elevated RNA expression.
To elucidate the basis of their efficient splicing, we examined their molecular architecture. Despite lacking globally stronger splice-site signals, short introns display a pronounced dependence on U2 snRNP–mediated 3′ splice-site recognition. Interactions of splicing factors that bridge snRNP components within a compact spliceosomal configuration are preferentially required for short intron processing, supporting a model in which efficient splicing relies on coordinated assembly within a spatially constrained architecture.
At the spatial level, short introns exhibit non-random higher-order organization. They cluster within chromosomes and transcripts and preferentially localize near nuclear speckles. GC-rich short introns are enriched in speckle-associated transcriptomes and splicing events, suggesting that nuclear compartmentalization enhances their processing efficiency.
Collectively, our results establish short introns as evolutionarily optimized architectural elements that coordinate compact spliceosomal assembly with genome organization and nuclear speckle localization, thereby reinforcing efficient and robust gene expression in humans.

 

Abstract: In the adult mammalian hippocampus, neurogenesis is concentrated in the subgranular zone of the dentate gyrus (DG). Adult-born neurons integrate functionally into existing hippocampal circuits, and dysregulation of adult hippocampal neurogenesis (AHN) is linked to disorders of learning, memory, and emotion. AHN declines with age. Our lab investigates how aging alters AHN in mice. We developed an efficient method to culture neurospheres from adult and aged DG neural progenitors, maintaining them as adult hippocampal neural progenitor cells (AHNPCs). We performed single-cell RNA sequencing on AHNPCs to identify intrinsic regulators of age-related changes. We transplanted AHNPCs into the mouse DG in vivo to assess their differentiation and integration in the mature hippocampus. Spatial transcriptomics showed that transplanted AHNPCs adopt expression profiles similar to those of neighboring endogenous granule cells. Ultimately, we aim to determine whether cultured AHNPCs can be used to treat neurological disorders.

Jen-Hsuan Wei
"From Cilia to Sperm: Decoding the Versatile Roles of SSNA1 Inside and Outside the Centrioles"

Abstract: Centrioles template the assembly of cilia and flagella, and dysfunction in these structures underlies a wide range of human ciliopathies. Yet, despite extensive structural insights, the distal lumen of the centriole remains a functionally enigmatic territory. We identify SSNA1 as a critical determinant of distal lumen organization and ciliogenesis, overturning the long-held view of SSNA1 as a microtubule-associated protein. Furthermore, its dynamic localization during spermatogenesis and its requirement for male fertility establish SSNA1 as a multifaceted regulator beyond centrioles, extending its influence from ciliary assembly to sperm development and illustrating how centriolar factors can be repurposed to support distinct physiological demands.

Jun-An Chen
"NcRNA in neural development, degeneration, and aging"

Abstract: The focus of research in my laboratory is to elucidate how neurons establish individual identity in the developing nervous system and why only specific neuron subtypes are vulnerable to neurodegenerative diseases. We tackle these questions by studying non-coding RNAs and their roles during motor neuron (MN) generation and degeneration. My lab uses mouse and human embryonic stem cells, induced pluripotent stem cells, and mouse/chicken animal models to investigate MN development and disease. We have developed a series of stem cell lines and animal models to study the functions of microRNAs and lncRNAs by “gain-of-function” and “loss-of-function” approaches. Further, we perform single-cell multiomics on healthy and ALS iPSC-derived MNs to functionally characterize non-coding RNA pathologies in MNs. In this talk, I will illustrate several new topics, including how lncRNA form condensates to perpetuate neuronal fate and the progress of the miRNAs and their application in MN diseases.

Suewei Lin
"The thirsty mind of the fruit fly: fromThe thirsty mind of the fruit fly: fromosmosensation to water-seeking motivation"

Abstract: To maintain body water homeostasis, the nervous system must monitor internal hydration andTo maintain body water homeostasis, the nervous system must monitor internal hydration anddrive water-seeking behavior when dehydration occurs. To understand the neural mechanismsunderlying body-water sensing and thirst-driven motivation, we study the nervous system ofthe fruit fly, where powerful genetic tools enable interrogation of neural circuits at single-cellresolution.We identified a pair of LHLK neurons in the fly brain that are activated by dehydration andpromote water-seeking behavior through the release of the neuropeptide leucokinin. Theseneurons detect dehydration by sensing increases in extracellular osmolality. This osmosensoryresponse requires the mechanosensory channel Pickpocket 26 (PPK26) and Ripped Pocket (RPK),the fly homolog of mammalian acid-sensing ion channels (ASICs).Leucokinin promotes water-seeking behavior by inhibiting two types of dopaminergic neuronsin the mushroom body (MB), a key computational center of the fly brain. These dopaminergicneurons encode the strength and specificity of water-seeking motivation.Together, our findings provide mechanistic insights into the neural basis of thirst, a fundamentalmotivational state conserved across the animal kingdom.