Biology subjects

Rathinam, D.

Publications and source records attributed to Rathinam, D..

2 recordsLinked to original sources

bioRxiv2025

CCB79 is a primate-specific cilium initiation factor essential to maintain neural progenitor diversity in developing brain tissue.

Identifying the genes that regulate the accurate spatiotemporal diversity of neural progenitor cells (NPCs) helps to understand the mechanisms of human neocortex expansion. In primate brains, an additional intermediate progenitor layer, the outer subventricular zone (oSVZ), facilitates the expansion of the neocortex. Here, we identify an uncharacterized gene, KIAA0408, and show that its expression is enriched in intermediate progenitors. Removing KIAA0408 in human-induced pluripotent stem cell (iPSC)-derived brain organoids results in an impaired cortical organization characterized by abnormal cell fate and patterning defects, including the depletion of intermediate and ventral progenitors. Molecularly, KIAA0408 codes for a 79-kilodalton centriolar distal appendage protein (DAP) that controls cilium biogenesis (hereafter CCB79). CCB79 forms a complex with other DAP components and specifically localizes in the DAP at the onset of ciliogenesis, and its absence blocks ciliogenesis. Mechanistically, progenitors in 3D brain tissues are unable to form cilia, which induces aberrant hedgehog signaling and causes premature differentiation. Finally, human CCB79, rather than the mouse ortholog, rescues cilia defects, suggesting that CCB79 has undergone rapid evolution from rodents to primates to fine-tune ciliogenesis for proper brain development.

neuroscience↗

bioRxiv2023

Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion, and drug screening

Brain organoids offer unprecedented insights into brain development and disease modeling and hold promise for drug screening. Significant hindrances, however, are morphological and cellular heterogeneity, inter-organoid size differences, cellular stress, and poor reproducibility. Here, we describe a method that reproducibly generates thousands of organoids across multiple iPSC lines. These High Quantity brain organoids (Hi-Q brain organoids) exhibit reproducible cytoarchitecture, cell diversity, and functionality, are free from ectopically active cellular stress pathways, and allow cryopreservation and re-culturing. Using patient-derived Hi-Q brain organoids, we recapitulated distinct forms of microcephaly pathogenesis: primary microcephaly due to a mutation in centrosomal CDK5RAP2 and progeria-associated microcephaly in Cockayne syndrome. When modeling glioma invasion, hi-Q brain organoids displayed a similar invasion pattern for a given patient-derived glioma cell line. This enabled a medium-throughput screen to identify Selumetinib and Fulvestrant, which also perturbed glioma invasion in vivo. Thus, the Hi-Q approach can easily be adapted to reliably harness brain organoids utility for personalized disease modeling and drug discovery.

cell biology↗