Autism spectrum disorder (ASD) is characterized by differences in social communication and restricted or repetitive behaviors, yet converging evidence also points to altered neural timing, synchronization, and large-scale coordination despite largely preserved gross neuroanatomy. Parallel observations across non-neural systems, including functional gastrointestinal disturbances, minor anomalies in neural crest–derived tissues, and variation in epithelial patterning outcomes, raise the possibility of a broader vulnerability in coordination-dependent biological processes. Here, we propose a framework in which developmental systems distinguish between spatial patterning mechanisms that establish tissue geometry and a calcium-dependent execution layer that stabilizes coordinated behavior across time. Patterning systems, including planar cell polarity signaling, morphogen gradients, and neural crest guidance cues, specify directional organization and spatial relationships among cells. Their realization, however, requires intracellular processes capable of synchronizing cytoskeletal remodeling, adhesion dynamics, excitability, and metabolic coupling across cells and networks. Within this framework, intracellular Ca²+ signaling – and particularly endoplasmic reticulum Ca²+ release mediated by inositol 1,4,5-trisphosphate receptors (ITPRs) – represents a candidate mechanism for stabilizing coordinated execution across biological systems. Partial disruption of this coordination layer could degrade synchronization, propagation, and temporal integration without abolishing underlying structural organization. This perspective provides a potential basis for linking altered cortical synchronization with coordination-dependent processes in enteric function, neural crest development, and epithelial patterning outcomes observed in ASD.This framework is not proposed as a universal explanation for ASD, but as a testable organizing model for coordination-related phenotypes across systems. By distinguishing spatial developmental instruction from the mechanisms that stabilize coordinated execution, this perspective generates experimentally tractable predictions across cellular, organoid, and systems-level models and offers a unifying framework for investigating coordination-dependent biology in ASD.
Radically different