title: A novel mouse model of tuberous sclerosis complex (TSC): eye-specific Tsc1-ablation disrupts visual-pathway development.
abstract: Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that is best characterised by neurodevelopmental deficits and the presence of benign tumours (called hamartomas) in affected organs. This multi-organ disorder results from inactivating point mutations in either the TSC1 or the TSC2 genes and consequent activation of the canonical mammalian target of rapamycin complex 1 signalling (mTORC1) pathway. Because lesions to the eye are central to TSC diagnosis, we report here the generation and characterisation of the first eye-specific TSC mouse model. We demonstrate that conditional ablation of Tsc1 in eye-committed progenitor cells leads to the accelerated differentiation and subsequent ectopic radial migration of retinal ganglion cells. This results in an increase in retinal ganglion cell apoptosis and consequent regionalised axonal loss within the optic nerve and topographical changes to the contra- and ipsilateral input within the dorsal lateral geniculate nucleus. Eyes from adult mice exhibit aberrant retinal architecture and display all the classic neuropathological hallmarks of TSC, including an increase in organ and cell size, ring heterotopias, hamartomas with retinal detachment, and lamination defects. Our results provide the first major insight into the molecular etiology of TSC within the developing eye and demonstrate a pivotal role for Tsc1 in regulating various aspects of visual-pathway development. Our novel mouse model therefore provides a valuable resource for future studies concerning the molecular mechanisms underlying TSC and also as a platform to evaluate new therapeutic approaches for the treatment of this multi-organ disorder.
authors.affiliation: Umeå Center for Molecular Medicine (UCMM), Umeå University, Umeå 901 87, Sweden.
authors.forename: Iwan
authors.initials: I
authors.lastname: Jones
authors.affiliation: Umeå Center for Molecular Medicine (UCMM), Umeå University, Umeå 901 87, Sweden.
authors.forename: Anna-Carin
authors.initials: AC
authors.lastname: Hägglund
authors.affiliation: Umeå Center for Molecular Medicine (UCMM), Umeå University, Umeå 901 87, Sweden.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Törnqvist
authors.affiliation: Umeå Center for Molecular Medicine (UCMM), Umeå University, Umeå 901 87, Sweden.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Nord
authors.affiliation: Umeå Center for Molecular Medicine (UCMM), Umeå University, Umeå 901 87, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Ahlgren
authors.affiliation: Umeå Center for Molecular Medicine (UCMM), Umeå University, Umeå 901 87, Sweden leif.carlsson@umu.se.
authors.forename: Leif
authors.initials: L
authors.lastname: Carlsson
mesh_terms: D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation; D002465:Cell Movement; D002467:Cell Nucleus / Q000473:pathology; D004195:Disease Models, Animal; D005123:Eye / Q000473:pathology*; D017353:Gene Deletion; D005911:Gliosis / Q000473:pathology; D006222:Hamartoma / Q000473:pathology; D007395:Interneurons / Q000378:metabolism; D018345:Mice, Knockout; D009030:Mosaicism; D016501:Neurites / Q000378:metabolism; D009900:Optic Nerve / Q000473:pathology; D009928:Organ Specificity; D012165:Retinal Ganglion Cells / Q000473:pathology; D014402:Tuberous Sclerosis / Q000473:pathology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014795:Visual Pathways / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology
chemical_list: C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins
keywords: Hamartoma; Retina; TSC