Whole-neuron morphology and genetic identity define cell types and reveal principles of brain-wide connectivity

Neocortex contains diverse excitatory neurons whose dendritic and axonal architectures shape computation and long-range communication, yet a unified framework linking neuronal structure, molecular identity, and brain-wide connectivity is lacking. Here, we combine complete whole-neuron morphology (WNM) reconstructions with paired genetic identities across 15 mouse cortical areas to define organizing principles of cortical wiring at single-cell resolution. We identify 10 stable excitatory cell types with conserved morphology and predominant genetic correspondence. Their full axonal target spectra reveal four output architectures and cell-type-resolved principles of corticocortical and cortico-subcortical organization, including modular convergence in downstream targets, distinct spatial topographical rules across corticocortical and corticofugal pathways, and hierarchical organization better predicted by targeting probability and projection distribution than projection strength, while refining bulk-derived projectomes by resolving artifacts from bulk approaches. Together, these findings establish WNM as a principled axis for defining cortical cell types as building blocks of large-scale connectomes.