Biology subjects

Bilheu, A.

Publications and source records attributed to Bilheu, A..

6 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↗

bioRxiv2022

LRRC37B is a species-specific regulator of voltage-gated channels and excitability in human cortical neurons

The enhanced cognitive abilities characterizing the human species result from specialized features of neurons and circuits, but the underlying molecular mechanisms remain largely unknown. Here we report that the hominid-specific gene LRRC37B encodes a novel receptor expressed in a subset of human cortical pyramidal neurons (CPNs). LRRC37B protein localizes at the axon initial segment (AIS), the specialized domain triggering action potentials. LRRC37B ectopic expression in mouse CPNs in vivo leads to reduced intrinsic excitability, a distinctive feature of some classes of human CPNs. At the molecular level, LRRC37B acts as a receptor for the secreted ligand FGF13A and interacts with the voltage gated sodium channel (VGSC) beta subunit SCN1B, thereby inhibiting the channel function of VGSC, specifically at the AIS. Electrophysiological recordings in adult human cortical slices reveals that endogenous expression of LRRC37B in human CPNs reduces neuronal excitability. LRRC37B thus acts as a species-specific modifier of human cortical neuron function, with important implications for human brain evolution and 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↗

bioRxiv2019

Xenotransplanted human cortical neurons reveal species-specific development and functional integration into mouse visual circuits.

How neural circuits develop in the human brain has remained almost impossible to study at the neuronal level. Here we investigate human cortical neuron development, plasticity and function, using a mouse/human chimera model in which xenotransplanted human cortical pyramidal neurons integrate as single cells into the mouse cortex. Combined neuronal tracing, electrophysiology, and in vivo structural and functional imaging revealed that the human neurons develop morphologically and functionally following a prolonged developmental timeline, revealing the cell-intrinsic retention of juvenile properties of cortical neurons as an important mechanism underlying human brain neoteny. Following maturation, human neurons transplanted in the visual cortex display tuned responses to visual stimuli that are similar to those of mouse neurons, indicating capacity for physiological synaptic integration of human neurons in mouse cortical circuits. These findings provide new insights into human neuronal development, and open novel experimental avenues for the study of human neuronal function and diseases.\n\nHighlightsO_LICoordinated morphological and functional maturation of ESC-derived human cortical neurons transplanted in the mouse cortex.\nC_LIO_LITransplanted neurons display prolonged juvenile features indicative of intrinsic species-specific neoteny.\nC_LIO_LITransplanted neurons develop elaborate dendritic arbors, stable spine patterns and long-term synaptic plasticity.\nC_LIO_LIIn the visual cortex transplanted neurons display tuned visual responses that resemble those of the host cortical neurons.\nC_LI

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↗