TAU, a microtubule-associated protein, encoded by the microtubule-associated protein tau (MAPT) gene, is a central regulator of microtubule stability and axonal function in the human brain, with its pathological aggregation representing a hallmark of Alzheimer's disease and related tauopathies. Despite extensive research into the role of TAU in neurodegeneration, its essentiality for human brain development has remained unclear. This perspective synthesizes recent genetic, molecular, and cellular evidence to demonstrate that the human brain-specific TAU isoform 0N3R is indispensable for proper neurodevelopment, pointing to loss-of-function of this isoform as a novel paradigm for TAU-associated disease. Alternative splicing of MAPT generates six brain-specific TAU isoforms, with 0N3R being exclusively expressed during fetal brain development. Analysis of large-scale human genetic datasets (gnomAD v4.0.0) reveals a high probability of loss-of-function intolerance (pLI = 0.96) for the 0N3R isoform. This is in stark contrast to the canonical Matched Annotation from the NCBI and EMBL-EBI (MANE) transcript and peripheral "Big TAU," both of which are tolerant to loss-offunction mutations. This intolerance is further supported by the scarcity of loss-of-function mutations in 0N3R-encoding exons and high missense constraint scores, suggesting strong evolutionary selection against disruption of this isoform. Functional studies using human induced pluripotent stem cell-derived cortical neurons with CRISPR-Cas9-mediated MAPT knockout reveal that, unlike in murine models where compensation by other microtubule-associated proteins occurs, loss of TAU in human neurons leads to deficits in neurite outgrowth, axon initial segment shortening, and a trend toward hyperexcitability, accompanied by broad transcriptomic changes affecting genes involved in microtubule organization and synaptic structure. Remarkably, re-expression of any of the six human brain-specific TAU isoforms rescues these phenotypes, underscoring their functional redundancy during development. These findings position the 0N3R isoform as essential for human brain development and suggest that loss-of-function mutations affecting this isoform likely result in neurodevelopmental impairment, potentially manifesting as intellectual disability without overt dysmorphic features. This contrasts with the apparent tolerance to MAPT loss-of-function in mice and peripheral tissues, highlighting a critical species- and isoform-specific requirement for TAU in human neurodevelopment. The hypothesis of 0N3R-TAU loss-of-function intolerance opens new avenues for understanding neurodevelopmental disorders and refines the conceptual framework of TAUassociated disease mechanisms beyond toxic gain-of-function.
