Biology subjects

Lago-Baldaia, I.

Publications and source records attributed to Lago-Baldaia, I..

4 recordsLinked to original sources

bioRxiv2025

Translation regulation of ATF4 by the termination complex Hbs1-Pelo is required for visual system development and function

Inherited retinal diseases are a class of genetically heterogenous disorders characterized by mutations in genes required for retinal function, resulting in progressive loss of vision in human patients. One such deletion mutation in the translation termination factor, HBS1L, results in a suite of developmental anomalies in human patients, including progressive vision loss defects. HBS1L, and its interaction partner Pelota (Pelo), are required for recycling stalled ribosomes on mRNAs, but the specific mRNA target causative of vision defects seen with HBS1L deletion remains unknown. Further, the specific cell types in the visual system that require HBS1L for proper development and function are also unknown. Here, we discover that loss of the Drosophila HBS1L homolog, Hbs1, results in reduced expression of the stress responsive Activating Transcription Factor 4 (ATF4) which is encoded by an mRNA containing multiple upstream open reading frames (uORFs) in its 5 leader. We corroborate these results in cultured human cells, where we find that HBS1L and Pelo promote translation reinitiation at the ATF4 ORF by facilitating proper translation termination at the preceding uORFs. Like human HBS1L deficiency patients, loss of function Drosophila mutants for Hbs1, pelo, and ATF4 show vision defects as measured by electroretinograms (ERG). Depleting Hbs1 in lamina neurons replicated the ERG defects seen in Hbs1 mutants, suggesting that Hbs1-Pelo is required for proper lamina neuron function. Further confocal analysis of Hbs1 mutants revealed vacuolization defects in the lamina layer, which are indicative of defective synapse formation between lamina neurons and photoreceptors. Strikingly, restoring ATF4 expression in the lamina partially rescued ERG defects in Hbs1 mutants, indicating that ATF4 is likely a relevant mRNA target regulated by Hbs1-Pelo in these cells. Together, our data support a model wherein Hbs1-Pelo mediated translation regulation of ATF4 in lamina neurons underlies the inherited retinal disease caused by HBS1L deletion.

genetics↗

bioRxiv2025

Morphogen and juxtacrine signalling dynamically integrate to specify cell fates with single-cell resolution

Morphogen gradients guide tissue patterning but do not act in isolation. How they integrate with other signalling modalities, like juxtacrine signalling, and how these integrations influence pattern resolution and robustness remain unclear. We address this in the Drosophila lamina, where columns of precursors are patterned with single-cell resolution into motion-processing neurons, dependent on a photoreceptor-derived Hedgehog gradient and glial-orchestrated differentiation. Combining experiments and theory, we show that glial-induced ERK activity drives Delta expression in lamina precursors, generating a graded Notch activity pattern. Notch restricts Hedgehog morphogen relay and enhances positional information. Glia act as timekeepers, scheduling ERK-driven differentiation after Hedgehog and Notch patterns are established. Thus, Notch and ERK dynamically integrate with Hedgehog to encode positional information, enabling reproducible cell fate patterning with single-cell resolution.

developmental biology↗

bioRxiv2022

A Drosophila glial cell atlas reveals that transcriptionally defined cell types can be morphologically diverse

Morphology is a defining feature of neuronal identity. Like neurons, glia display diverse morphologies, both across and within glial classes, but are also known to be morphologically plastic. Here, we explored the relationship between glial morphology and transcriptional signature using the Drosophila central nervous system, where glia are categorized into five main classes (outer and inner surface glia, cortex glia, ensheathing glia, and astrocytes), which show within-class morphological diversity. We analysed and validated single cell RNA sequencing data of Drosophila glia in two well-characterized tissues from distinct developmental stages, containing distinct circuit types: the embryonic ventral nerve cord (motor) and the adult optic lobes (sensory). Our analysis identified a new morphologically and transcriptionally distinct surface glial population in the ventral nerve cord. However, many glial morphological categories could not be distinguished transcriptionally, and indeed, embryonic and adult astrocytes were transcriptionally analogous despite differences in developmental stage and circuit type. While we did detect extensive within-class transcriptomic diversity for optic lobe glia, this could be explained entirely by glial residence in the most superficial neuropil (lamina) and an associated enrichment for immune-related gene expression. In summary, we generated a single-cell transcriptomic atlas of glia in Drosophila, and our extensive in vivo validation revealed that glia exhibit more diversity at the morphological level than was detectable at the transcriptional level. This atlas will serve as a resource for the community to probe glial diversity and function.

neuroscience↗

bioRxiv2021

Differentiation signals from glia are fine-tuned to set neuronal numbers during development

Neural circuit formation and function require that diverse neurons are specified in appropriate numbers. Known strategies for controlling neuronal numbers involve regulating either cell proliferation or survival. We used the Drosophila visual system to probe how neuronal numbers are set. Photoreceptors from the eye-disc induce their target field, the lamina, such that for every unit eye there is a corresponding lamina unit (column). Although each column initially contains [~]6 post-mitotic lamina precursors, only 5 differentiate into neurons, called L1-L5; the extra precursor, which is invariantly positioned above the L5 neuron in each column, undergoes apoptosis. Here, we showed that a glial population called the outer chiasm giant glia (xgO), which resides below the lamina, secretes multiple ligands to induce L5 differentiation in response to EGF from photoreceptors. By forcing neuronal differentiation in the lamina, we uncovered that though fated to die, the extra precursor is specified as an L5. Therefore, two precursors are specified as L5s but only one differentiates during normal development. We found that the row of precursors nearest to xgO differentiate into L5s and, in turn, antagonise differentiation signalling to prevent the extra precursors from differentiating, resulting in their death. Thus, an intricate interplay of glial signals and feedback from differentiating neurons defines an invariant and stereotyped pattern of neuronal differentiation and programmed cell death to ensure that lamina columns each contain exactly one L5 neuron.

developmental biology↗