Modeling idiopathic autism in forebrain organoids reveals an imbalance of excitatory cortical neuron subtypes during early neurogenesis

A foundational atlas of autism protein interactions reveals molecular convergence

“…The differential expression patterns of FOXP1, FOXP2 (broad expression) and FOXP4 (highly enriched in NPCs and early postmitotic neurons during deep cortical layer neurogenesis) 62,145 in the developing forebrain and their potential impact on deep layer-like cell differentiation due to changes in DNA binding could be significant, but will require further confirmation using orthogonal models. Notably, similar alterations in deep cortical layer and subplate neuron differentiation have been reported in the study of idiopathic ASD patient-derived brain organoids 146 . It is important to note, however, that studies of ASD mutations using organoids are inherently limited by the virtue of their in vitro nature.…”

Protein expression profiles in brain organoids are more similar to those in human brain parenchyma than in mouse brain parenchyma

“…Our data demonstrate that BOs derived from familial iPSCs (healthy donors) develop proteins at similar time-points, supporting other studies that show cell composition of BOs are predominately driven by the genetic differences of iPSCs from different families (Jourdon et al, 2023). Our data further corroborates the findings of Jourdon et al (2023) by showing minimal batch-to-batch variability as measured by several different assays, including total protein, resazurin reduction, and expression of housekeeping genes. Importantly, this reproducible consistency occurs without compromising the original visual developmental hallmarks of BOs (Lancaster and Knoblich, 2014).…”

“…Consistent with other studies, several isoforms of GFAP were detected in human parenchymal tissues and fewer isoforms were detected in mouse Ctx tissues (Kamphuis et al, 2014, 2012), highlighting interspecies differences. Further studies with a much larger cohort of familial iPSC lines are needed to determine whether BOs have the capacity to retain the donor heterogeneity that we observe in human parenchymal samples, but the transcriptomic study by Jourdon et al (2023) indicates that at least some donor heterogeneity is retained in BO cultures. It would be exciting if future studies show BOs derived from different donors could capture the heterogeneity of GFAP isoform expression that we observe in human parenchymal tissues.…”

“…BOs have been described to be human brain-like tissues that exhibit batch- and cell line-dependent variability (Kim et al, 2021), but studies using stringent protocols demonstrate the variability may not be as pronounced as originally hypothesized given adequate study design (Jourdon et al, 2023; Velasco et al, 2019). A majority of studies have compared the transcriptome of BOs to those of adult and fetal parenchymal tissues (Velasco et al, 2019), but these analyses often do not account for the different proteoforms (e.g., splice isoforms and post-translational modifications) of any given protein.…”

“…Furthermore, we compare the levels of several proteins in human BOs, human and mouse Ctx tissue as well as human Cb tissue derived from male and female donors. BOs were generated from the induced pluripotent stem cells (iPSCs) of female-male sibling donors because familial cell lines are known to result in more similar organoids (Jourdon et al, 2023). Our data corroborate these previously reported data as we observed limited variability between our batches of human BOs, and interestingly, these in vitro cultures display less protein variability between samples than the human and mouse parenchymal tissues.…”