Pathological priming causes developmental gene network heterochronicity in autistic subject-derived neurons

Abstract

Autism spectrum disorder (ASD) is thought to emerge during early cortical development. However, the exact developmental stages and associated molecular networks that prime disease propensity are elusive. To profile early neurodevelopmental alterations in ASD with macrocephaly, we monitored patient-derived induced pluripotent stem cells (iPSCs) throughout the recapitulation of cortical development. Our analysis revealed ASD-associated changes in the maturational sequence of early neuron development, involving temporal dysregulation of specific gene networks and morphological growth acceleration. The observed changes tracked back to a pathologically primed stage in neural stem cells (NSCs), reflected by altered chromatin accessibility. Concerted overrepresentation of network factors in control NSCs was sufficient to trigger ASD-like features, and circumventing the NSC stage by direct conversion of ASD iPSCs into induced neurons (iPSC-iNs) abolished ASD-associated phenotypes. Our findings identify heterochronic dynamics of a gene network that, while established earlier in development, contributes to subsequent neurodevelopmental aberrations in ASD.

Blood platelet research in autism spectrum disorders: In search of biomarkers

“…75,79 This was confirmed in hippocampal neurons in sleepdeprived mice. 78,79 Therefore, increased platelet NAS could echo its levels in the CNS, which in turn supports an abnormal growth acceleration in neural precursor cells from ASD cases as observed in a study by Schafer et al 80 Platelet NAS should be measured in larger ASD cohorts in addition to 5-HT to evaluate its potential as an ASD biomarker.…”

Next‐generation disease modeling with direct conversion: a new path to old neurons

“…While this study did not assess any age-related differences between patientand control-derived induced motor neurons, an impressive study by Victor et al [7] demonstrated the importance of modeling old age as a disease-relevant factor in a model consisting of both iPSC-derived and fibroblast-derived medium spiny iNs. As opposed to the most widely believed assumption that the first disease phenotypes emerge in immature neurons, they found heterochronic trajectories in patient cells that were already epigenetically primed for acceleration at the neural stem cell stage [16]. In consistence with the observation that HD iPSC-derived neurons need external stressors to display this disease phenotype, the authors showed that an age-related collapse in proteostasis triggered huntingtin aggregation in an age-and repeat-lengthdependent manner [7].…”

“…Thus, neuronal subtype specification cannot be easily achieved through the addition of patterning factors such as Wnt or Shh in the media, because the responsive cell type is not present at any time point during conversion. For example, iNs generated from iPSCs through Ngn2-only protocols are predominantly glutamatergic [16,68]. 1B) [25,26,31].…”

“…This boom in applications can be mostly attributed to the explosion of new technologies tailored to iPSC-based systems, most of which are also suitable for directly converted cells. These technologies encompass tools and strategies to harness human donor/patient-specific cells for basic human biology research [9][10][11][12], disease modeling [13][14][15][16][17], drug development and safety [18][19][20][21], or cell replacement strategies [22]. Although on first sight iNs might appear as 'just another way' to generate neurons in the dish, there are important technical and conceptual differences between iPSC-derived neurons and iNs to be noted.…”

Grow your own brain

“…A recent study from the SALK institute (CA, USA) did just that, and demonstrated that neurons derived from skin cells of individuals with autism spectrum disorder (ASD) show different patterns of development and growth when compared with cells of neurotypical individuals [3]. …”