Biology subjects

Jabali, A.

Publications and source records attributed to Jabali, A..

4 recordsLinked to original sources

bioRxiv2026

A defined 2D system for generating and expanding human basal radial glia from iPSCs

Basal radial glia (bRG) drive human cortical expansion but remain underrepresented in vitro. We established a defined and expandable 2D system for efficient generation of human bRG from iPSCs. These cells recapitulate canonical molecular signatures, hallmark somal translocation behaviours, intrinsic differentiation potential, and integration into organoid tissue. Network-based analyses identified PAK2 as a regulator of mitotic somal translocation, illustrating the systems utility for mechanistic interrogation of bRG biology.

neuroscience↗

bioRxiv2026

Serotonergic innervation and cortical progenitor regulation in human brain assembloids

Neuromodulatory signaling is classically associated with mature neural circuits, yet serotonergic projections reach the developing cortex prior to circuit formation, suggesting a role in early human cortical development. Here, we establish a human raphe-cortical assembloid platform by generating iPSC-derived hindbrain-patterned raphe organoids that produce serotonergic neurons and form projections into fused cortical organoids, exhibiting endogenous serotonin release within developing cortical tissue. Using this system, we find that serotonergic innervation is associated with a shift toward progenitor-enriched states, accompanied by increased proliferative activity, activation of developmental transcriptional programs, and predicted signaling interactions targeting cortical progenitors and neurons. Consistent with these findings, cortical regions receiving serotonergic projections exhibit increased mitotic activity, and pharmacological modulation demonstrates selective proliferative responses in basal progenitor populations, consistent with observations in human fetal tissue. Together, this system provides a framework to investigate how early neuromodulatory input shapes human cortical development and developmental vulnerability.

neuroscience↗

bioRxiv2024

A high-throughput zebrafish screen identifies novel candidate treatments for Kaposiform Lymphangiomatosis (KLA)

Kaposiform Lymphangiomatosis (KLA) is a rare, aggressive, and incurable disease caused by a somatic activating NRAS mutation (p.Q61R) in lymphatic endothelial cells (LECs). The development of new therapeutic avenues is hampered by the lack of animal models faithfully replicating the clinical manifestations of KLA. Here, we established a novel zebrafish model of KLA by driving conditional expression of the human NRAS mutation in venous and lymphatic ECs. We find that mutant embryos recapitulated clinical features of KLA, including pericardial edema and a dilated thoracic duct, and that the phenotypes were reverted by Trametinib, a MEK inhibitor used for KLA treatment. We further leverage this model in combination with an AI-based high-throughput drug screening platform to search for small compounds selectively reverting the mutant phenotypes and identify Cabozantinib, an FDA-approved tyrosine kinase inhibitor, and GSK690693, a competitive pan-Akt kinase inhibitor, as leading hits. Finally, we test these drugs in cultured cells derived from KLA patient and demonstrate their ability to normalize LEC sprouting and block NRAS downstream pathways, underscoring the potential of GSK690693 and Cabozantinib as potential KLA treatments. Overall, our novel zebrafish model provides a valuable tool for research into the etiology of KLA and for identifying new therapeutic avenues.

developmental biology↗

bioRxiv2022

Capturing the pathomechanisms of different disease severities in a human cerebral organoid model of LIS1-lissencephaly

Lissencephaly is a malformation of cortical development (MCD) characterized by reduced to absent gyri and a disorganized cortex, leading to severe neurological consequences in affected individuals, including epilepsy, intellectual disability, and reduced life expectancy. Treatments are purely symptomatic, and patients often remain refractory to them. Heterozygous mutations in the LIS1 gene, encoding a regulator of the microtubule motor dynein, cause LIS1-lissencephaly. For unknown reasons, LIS1-lissencephaly patients show marked differences in disease severity despite each carrying a heterozygous LIS1 mutation. We leveraged forebrain-type organoids from patients diagnosed with mild, moderate, or severe LIS1-lissencephaly to investigate, in a cytoarchitecture and multi-omics approach, disease and severity grade associated phenotypes, mechanisms, and rescue approaches. We identified alterations of the cytoarchitecture, progenitor cell homeostasis, and neurogenesis often with a severity-dependent gradient. Identified disease-linked molecular mechanisms were microtubule destabilization, WNT-signaling, protein metabolism, and perturbed cadherin- and unfolded protein-binding. Some mechanisms exhibited a severity-dependent gradient or were specific to a severe grade. We present strategies to reverse phenotypic changes in LIS1-patient organoids and identify mTOR pathway inhibitors in in silico drug repurposing analysis as potential novel therapeutic strategy. By probing the top hit drug, the mTOR inhibitor everolimus, we could indeed rescue severity-dependent phenotypic changes in LIS1-patient organoids. This study demonstrates that organoid-based modeling is sensitive in recapitulating disease severity, which presents an important step in patient stratification, and allows the development of novel personalized rescue strategies with therapeutic potential.

neuroscience↗