Biology subjects

Ditkowska, M.

Publications and source records attributed to Ditkowska, M..

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↗

bioRxiv2023

Human synaptic neoteny requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition

Human-specific (HS) genes are potential drivers of brain evolution, but their impact on human neuron development and disease remains unclear. Here we studied HS genes SRGAP2B/C in human cortical projection neurons (CPNs) in vivo, using xenotransplantation in the mouse cortex. Downregulation of SRGAP2B/C in human CPNs greatly accelerated synaptic development, indicating their requirement for human-specific synaptic neoteny. SRGAP2B/C acted by downregulating their ancestral paralog SRGAP2A, thereby upregulating postsynaptic levels of SYNGAP1, a major intellectual deficiency/autism spectrum disorder (ID/ASD) gene. Combinatorial genetic invalidation revealed that the tempo of synaptogenesis is set by a balance between SRGAP2A and SYNGAP1, which in human CPNs is tipped towards neoteny by SRGAP2B/C. Our results demonstrate that HS genes can modify the phenotypic expression of ID/ASD mutations through regulation of synaptic neoteny. One-Sentence SummaryHuman-specific genes SRGAP2B/C control human cortical neuron neoteny by regulating the function of neurodevelopmental disorder gene SYNGAP1

neuroscience↗

bioRxiv2023

SYNGAP1 deficiency disrupts neoteny in human cortical neurons in vivo.

Intellectual deficiency (ID) and autism spectrum disorder (ASD) originate from disrupted development of human-specific cognitive functions. Human brain ontogeny is characterized by a considerably prolonged, neotenic, cortical neuron development. Neuronal neoteny could be disrupted in ID/ASD, but this was never tested because of the difficulties to study developing human cortical circuits. Here we use xenotransplantation of human cortical neurons into the mouse cortex to study the in vivo neuronal consequences of SYNGAP1 haploinsufficiency, a frequent cause of ID/ASD. We find that SYNGAP1 deficient neurons display strong acceleration of morphological and functional synaptic development. At the circuit level, SYNGAP1 haploinsufficient neurons display disrupted neoteny, with faster integration into cortical circuits and acquisition of sensory responsiveness months ahead of time. These data link neuronal neoteny to ID/ASD, with important implications for diagnosis and treatments.

neuroscience↗

bioRxiv2021

Species-specific mitochondria dynamics and metabolism regulate the timing of neuronal development

The evolution of species involves changes in the timeline of key developmental programs. Among these, neuronal development is considerably prolonged in the human cerebral cortex compared with other mammals, leading to brain neoteny. Here we explore whether mitochondria influence the species-specific properties of cortical neuron maturation. By comparing human and mouse cortical neuronal maturation at high temporal and cell resolution, we found a slower pattern of mitochondria development in human cortical neurons compared with the mouse, together with lower mitochondria metabolic activity, particularly oxidative phosphorylation. Stimulation of mitochondria metabolism in human neurons resulted in accelerated maturation, leading to excitable and complex cells weeks ahead of time. Our data identify mitochondria as important regulators of the pace of neuronal development underlying human-specific features of brain evolution.

neuroscience↗