Biology subjects

Limame, R.

Publications and source records attributed to Limame, R..

3 recordsLinked to original sources

bioRxiv2025

Species-specific Rates of Fatty Acid MetabolismSet the Scale of Temporal Patterning of Corticogenesisthrough Protein Acetylation Dynamics

Developmental processes display temporal differences across species, leading to divergence in organ size and composition. In the cerebral cortex, neurons of diverse identities are generated sequentially through a temporal patterning mechanism conserved throughout mammals. This corticogenesis process is considerably prolonged in the human species, leading to increased brain size and complexity, but the underlying molecular mechanisms remain largely unknown. Here we found that human cortical progenitors displayed lower levels of fatty acid oxidation than their mouse counterparts, in line with their protracted pattern. Treatments that enhance mitochondrial fatty acid oxidation (FAO) accelerated the development of human cortical organoids, including faster progression of neural progenitor cell fate and precocious generation of late-born neurons and glia. FAO accelerated temporal patterning through increased Acetyl-CoA-dependent protein acetylation, including on specific histone transcriptional marks. Thus, species-specific metabolic rates regulate the turnover of post-translation modifications to set the scale of temporal gene regulatory networks of corticogenesis.

neuroscience↗

bioRxiv2023

The microcephaly gene ASPM is required for the timely generation of human outer-radial glia progenitors by controlling mitotic spindle orientation

Abnormal spindle-like, microcephaly-associated (ASPM) is the most commonly mutated gene in primary microcephaly (MCPH), characterized by reduced brain size and intellectual deficiency. The mechanisms underlying MCPH have remained unclear, as ASPM disruption leads to distinct phenotypes depending on the species studied. Here, we studied the impact of ASPM pathogenic mutations on human corticogenesis in organoid models. We found that at earliest stages of neurogenesis, ASPM mutant cortical progenitors, located at the apical surface of the neuroepithelium, display transient mitotic spindle randomization. The mutant progenitors then delaminate basally to adopt precociously the characteristics of outer radial glia cells (oRGC), a population of progenitors selectively amplified in human corticogenesis. Subsequently, cortical progenitors are depleted through decreased amplification and increased apoptosis. Thus, ASPM regulates the timely generation of oRGC by controlling mitotic spindle orientation, shedding light on how species-specific features of neurogenesis may confer vulnerability to neurodevelopmental diseases.

neuroscience↗

bioRxiv2021

The Amyloid Precursor Protein regulates human cortical neurogenesis

The approximately 16 billion neurons of the human neocortex are derived from a relatively limited number of developmental neural stem cells (NSCs). During embryogenesis, human cortical NSCs initially generate neurons at a particularly slow rate while preserving their progenitor state for a relatively long time. How this balance between the progenitor state and neurogenic state is regulated, and whether it contributes to species-specific brain patterning, is poorly understood. Here we show that the characteristic potential of human NSCs to remain in a progenitor state as they generate neurons for a prolonged amount of time requires the Amyloid Precursor Protein (APP). In contrast, APP is dispensable in mouse NSCs, which undergo neurogenesis at a much faster rate. Mechanistically, loss of APP cell-autonomously accelerates neurogenesis through activation of the AP1 transcription factor and repression of WNT signaling. We propose that the fine balance between self-renewal and differentiation is homeostatically regulated by APP, which may contribute to human-specific temporal patterns of neurogenesis.

developmental biology↗