Biology subjects

Ahluwalia, R.

Publications and source records attributed to Ahluwalia, R..

3 recordsLinked to original sources

bioRxiv2025

A stress-dependent postembryonic role for the core CPA factor CFIM-1 in germline integrity

Post-transcriptional processing of pre-mRNAs generates a diversity of 3 UTR transcript isoforms that can vary in their function and stability. The differential enrichment of transcript isoforms has been implicated in diseases ranging from cancer to neurodevelopmental disorders. However, the post-embryonic developmental roles of the core ensemble of cleavage and polyadenylation (CPA) factors that mediate these post-transcriptional changes remain poorly characterized. Here, we report a stress- dependent role for the core CPA factor CFIM-1 in germline integrity in Caenorhabditis elegans. Total loss-of-function of cfim-1 elicits a temperature-sensitive sterile phenotype in hermaphrodites. These changes in brood size are accompanied by broad sperm, oocyte and germline morphology defects. Surveying the transcriptome of cfim-1(lf) worms, we uncover changes in transcript isoform abundance for dozens of genes with known functions related to the development and maintenance of these structures, consistent with a model in which post-transcriptional regulation of target genes via cfim- 1 is crucial to the development and maintenance of germline integrity. Our findings collectively define a novel post-embryonic role for a core CPA factor in tissue-specific development.

developmental biology↗

bioRxiv2025

BRCA1 is a molecular correlate of cell proliferation in human brain development and in Group 3 and 4 medulloblastoma

The role of the BRCA1-mediated DNA damage repair pathway in regulating human brain development remains unknown, although it has been studied in mouse development. We report evidence for breast cancer type 1 susceptibility protein (BRCA1) being a molecular correlate of proliferation in human neural progenitor cells and in medulloblastoma (MB), a malignant pediatric hindbrain cancer whose cells resemble undifferentiated neural stem cells. In a computational search for molecules potentially keeping Group 3 (G3) and Group 4 (G4) MB tumour cells in a state of stalled differentiation, BRCA1 emerged as a leading candidate gene. We surveyed four independent transcriptomic datasets collectively spanning 142 human developing brain samples, multiple brain regions, and over 1.7 million single cells, and found that BRCA1 transcription is consistently enriched in human neural stem and progenitor cells, relative to differentiating or mature neurons. Across the human lifespan, BRCA1 expression is enriched in the brain during early development, particularly the first trimester of gestation. By analyzing 714 tumours, the largest transcriptomic survey of MB tumours to date, we found that BRCA1 expression is increased in carriers of isochromosome 17q (i17q) aberrations and in G4 MB tumours. Increased BRCA1 expression is associated with worse prognosis in G3 and G4 MB. In the developing cerebellum as well as in the cancer context, BRCA1 expression is correlated with transcription of the cell cycle and DNA damage repair pathways. When considered with previous mouse studies, our work is consistent with a model in which BRCA1 promotes genome surveillance in neural progenitors during human brain development and in G3 and G4 MB tumour growth, thus supporting proliferation.

genomics↗

bioRxiv2019

Presynaptic MAST Kinase Controls Bidirectional Post-SynapticResponses to Convey Stimulus Valence in C. elegans

Presynaptic plasticity is known to modulate the strength of synaptic transmission. However, it remains unknown whether regulation in presynaptic neurons alters the directionality -positive or negative-of postsynaptic responses. We report here that the C. elegans homologs of MAST kinase, Stomatin and Diacylglycerol kinase act in a thermosensory neuron to elicit in its postsynaptic neuron an excitatory or inhibitory response that correlates with the valence of thermal stimuli. By monitoring neural activity of the valence-coding interneuron in freely behaving animals, we show that the alteration between excitatory and inhibitory responses of the interneuron is mediated by controlling the balance of two opposing signals released from the presynaptic neuron. These alternative transmissions further generate opposing behavioral outputs necessary for the navigation on thermal gradients. Our findings reveal the previously unrecognized capability of presynaptic regulation to evoke bidirectional postsynaptic responses and suggest a molecular mechanism of determining stimulus valence.

neuroscience↗