Loss of function of the tuberous sclerosis 2 tumor suppressor gene resultsin embryonic lethality characterized by disrupted neuroepithelial growth and development

Germline defects in the tuberous sclerosis 2 (TSC2) tumor suppressor gene p redispose humans and rats to benign and malignant lesions in a variety of t issues. The brain is among the most profoundly affected organs in tuberous sclerosis (TSC) patients and is the site of development of the cortical tub ers for which the hereditary syndrome is named. A spontaneous germline inac tivation of the Tsc2 locus has been described in an animal model, the Eker rat. We report that the homozygous state of this mutation (TsC2(Ek/Ek)) was lethal in mid-gestation (the equivalent of mouse E9.5-E13.5), when Tsc2 mR NA was highly expressed in embryonic neuroepithelium. During this period ho mozygous mutant Eker embryos lacking functional Tsc2 gene product, tuberin, displayed dysraphia and papillary overgrowth of the neuroepithelium, indic ating that loss of tuberin disrupted the normal development of this tissue. Interestingly, there was significant intraspecies variability in the penet rance of cranial abnormalities in mutant embryos: the Long-Evens strain Tsc 2(Ek/Ek) embryos displayed these defects whereas the Fisher 344 homozygous mutant embryos had normal appearing neuroepithelium. Taken together, our da ta indicate that the Tsc2 gene participates in normal brain development and suggest the inactivation of this gene may have similar functional conseque nces in both mature and embryonic brain.