Biology subjects

Louvi, A.

Publications and source records attributed to Louvi, A..

3 recordsLinked to original sources

bioRxiv2022

Microcephaly-associated WDR62 mutations hamper Golgi apparatus-to-spindle pole shuttling in human neural progenitors

WDR62 is a spindle pole-associated scaffold protein with pleiotropic functions during corticogenesis. Recessive mutations in WDR62 are associated with structural brain abnormalities and account for the second most common cause of autosomal recessive primary microcephaly (MCPH), indicating WDR62 as a critical hub for human brain development. Here, we investigated a C-terminal truncating mutation (D955AfsX112) in WDR62 using induced pluripotent stem cells (iPSCs) obtained from a patient with MCPH2. We generated neuroepithelial stem (NES) cells and cerebro-cortical progenitors and neurons from patient-derived and isogenic retro-mutated iPSC lines. We found that WDR62 dysfunction resulted in impaired cell cycle progression and alterations of the neurogenic trajectories of iPSC neuroderivatives. Moreover, we report WDR62 localization at the Golgi apparatus during interphase, both in human neural progenitors in vitro and in human fetal brain tissue. WDR62 shuttling from the Golgi apparatus to spindle poles is dynamic and microtubule-dependent. Impairment of WDR62 function and localization results in severe neurodevelopmental abnormalities, thus delineating new mechanisms in MCPH etiology.

neuroscience↗

bioRxiv2019

The Human Accelerated Region HACNS1 modifies developmental gene expression in humanized mice

The evolution of uniquely human traits likely entailed changes in developmental gene regulation. Human Accelerated Regions (HARs), which include transcriptional enhancers harboring a significant excess of human-specific sequence changes, are leading candidates for driving gene regulatory modifications in human development. However, insight into whether HARs alter the level, distribution and timing of endogenous gene expression remains limited. We examined the role of the HAR HACNS1 (HAR2) in human evolution by interrogating its molecular functions in a humanized mouse model. We find that HACNS1 maintains its human-specific enhancer activity in humanized mice and that it modifies expression of Gbx2, which encodes a homeobox transcription factor, during limb development. Using single-cell RNA-sequencing, we demonstrate that Gbx2 is upregulated in the chondrogenic mesenchyme of humanized limbs, supporting that HACNS1 alters gene expression in cell types involved in skeletal patterning. Our findings illustrate that humanized mouse models provide mechanistic insight into how HARs modified gene expression in human evolution.

genetics↗

bioRxiv2018

Notch2 signaling regulates Id4 and cell cycle genes to maintain neural stem cell quiescence in the adult hippocampus

Neural stem cells (NSCs) in the adult hippocampal dentate gyrus (DG) can be quiescent or proliferative, but how they are maintained is largely unknown. With age DG NSCs become increasingly dormant, which impinges on neuron generation. We addressed how NSC activity is controlled and found that Notch2 promotes quiescence by regulating their transition to the activated state. Notch2-ablation induces cell cycle genes and markers of active NSCs. Conversely, quiescent NSC-associated genes, including Id4, are down regulated after Notch2 deletion. We found that Notch2 binds the Id4 promoter and positively regulates transcription. Similar to Notch2, Id4 overexpression promotes DG NSC quiescence and Id4 knockdown rescues proliferation, even when Notch2 signaling is activated. We show that Notch2 regulates age-dependent DG NSC dormancy and Notch2 inhibition rejuvenates neurogenesis in the DG of aged mice. Our data indicate that a Notch2-Id4 axis promotes adult DG NSC quiescence and dormancy.

neuroscience↗