Whether the cell nucleus is organized by an underlying architecture analago
us to the cytoskeleton has been a highly contentious issue since the origin
al isolation of a nuclease and salt-resistant nuclear matrix. Despite elect
ron microscopy studies that show that a nuclear architecture can be visuali
zed after fractionation, the necessity to elute chromatin to visualize this
structure has hindered general acceptance of a karyoskeleton. Using an ana
lytical electron microscopy method capable of quantitative elemental analys
is, electron spectroscopic imaging, we show that the majority of the fine s
tructure within interchromatin regions of the cell nucleus in fixed whole c
ells is not nucleoprotein. Rather, this fine structure is compositionally s
imilar to known protein-based cellular structures of the cytoplasm. This st
udy is the first demonstration of a protein network in unfractionated and u
ninfected cells and provides a method for the ultrastructural characterizat
ion of the interaction of this protein architecture with chromatin and ribo
nucleoprotein elements of the cell nucleus.