Biology subjects

Herpoel, A.

Publications and source records attributed to Herpoel, A..

4 recordsLinked to original sources

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↗

bioRxiv2020

CROCCP2 acts as a human-specific modifier of cilia dynamics and mTOR signalling to promote expansion of cortical progenitors.

The primary cilum is a central component of signalling during neural development, from regional patterning to neuronal differentiation. Here we focus on CROCCP2, a hominid-specific gene duplicate from CROCC (Ciliary Rootlet Coiled Coil), also known as rootletin, that encodes the major protein component of the ciliary rootlet. We find that CROCCP2 is highly expressed in the human fetal brain and not in other primate species. CROCCP2 gain of function in the mouse embryonic cortex results in decreased ciliogenesis, increased mTOR signalling, and increased cell size of radial glial cells, leading to increased generation of intermediate/basal progenitors and increased neuronal output. CROCCP2 impacts cilia dynamics and neurogenesis by inhibition of the IFT20 ciliary trafficking protein. Our data identify a human-specific protein that drives cortical basal progenitor expansion through modulation of ciliary dynamics.

neuroscience↗

bioRxiv2018

Bcl6 promotes neurogenic conversion through transcriptional repression of multiple self-renewal-promoting extrinsic pathways.

During neurogenesis, progenitors switch from self-renewal to differentiation through the interplay of intrinsic and extrinsic cues, but how these are integrated remains poorly understood. Here we combine whole genome transcriptional and epigenetic analyses with in vivo functional studies and show that Bcl6, a transcriptional repressor known to promote neurogenesis, acts as a key driver of the neurogenic transition through direct silencing of a selective repertoire of genes belonging to multiple extrinsic pathways promoting self-renewal, most strikingly the Wnt pathway. At the molecular level, Bcl6 acts through both generic and pathway-specific mechanisms. Our data identify a molecular logic by which a single cell-intrinsic factor ensures robustness of neural cell fate transition by decreasing responsiveness to the extrinsic pathways that favor self-renewal.

neuroscience↗

bioRxiv2017

Hominin-specific NOTCH2 paralogs expand human cortical neurogenesis through regulation of Delta/Notch interactions.

The human cerebral cortex has undergone rapid expansion and increased complexity during recent evolution. Hominid-specific gene duplications represent a major driving force of evolution, but their impact on human brain evolution remains unclear. Using tailored RNA sequencing (RNAseq), we profiled the spatial and temporal expression of Hominid-specific duplicated (HS) genes in the human fetal cortex, leading to the identification of a repertoire of 36 HS genes displaying robust and dynamic patterns during cortical neurogenesis. Among these we focused on NOTCH2NL, previously uncharacterized HS paralogs of NOTCH2. NOTCH2NL promote the clonal expansion of human cortical progenitors by increasing self-renewal, ultimately leading to higher neuronal output. NOTCH2NL function by activating the Notch pathway, through inhibition of Delta/Notch interactions. Our study uncovers a large repertoire of recently evolved genes linking genomic evolution to human brain development, and reveals how hominin-specific NOTCH paralogs may have contributed to the expansion of the human cortex.

developmental biology↗