Abstract
ABSTRACTTuberous 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.
Highlights
Genetic disruption during the formation of the central nervous system (CNS) is one of the underlying causes of neurodevelopmental deficits; the incidence rate of such disruptions is high within multi-organ syndromes such as tuberous sclerosis complex (TSC) (OMIM191100) (Han and Sahin, 2011; Smalley, 1998; Thiele, 2004)
Conditional deletion of Tsc1 leads to enlarged eyes, hamartomas and loss of retinal architecture We first examined the morphology of the eye in Lhx2-Cre:Tsc1f/f mice, because hamartoma formation is one of the pathological hallmarks of Tuberous sclerosis complex (TSC) (Samueli et al, 2015)
The mutant mice described in this report differ substantially from the majority of published TSC models because we ablated Tsc1 during early embryonic development in a progenitor cell population that generates both neural and glial lineages within the retina. This is in contrast to previous studies where the Tsc1 or Tsc2 genes have been ablated during later embryonic development in either neuronal or glial lineages independently (Ehninger et al, 2008; Feliciano et al, 2012; Meikle et al, 2007; Uhlmann et al, 2002; Way et al, 2009; Zeng et al, 2011; Zhou et al, 2011)
Summary
Genetic disruption during the formation of the central nervous system (CNS) is one of the underlying causes of neurodevelopmental deficits; the incidence rate of such disruptions is high within multi-organ syndromes such as tuberous sclerosis complex (TSC) (OMIM191100) (Han and Sahin, 2011; Smalley, 1998; Thiele, 2004). The protein products of TSC1 and TSC2 (hamartin and tuberin, respectively) form a heterodimeric complex that is stabilised by a third protein partner (TBC17D) This complex negatively regulates cell growth and proliferation through a canonical signalling pathway. Individuals with TSC present with a myriad of complex neurological deficits, with autism and epilepsy being prevalent amongst affected individuals. These observations clearly demonstrate that TSC is a multifaceted syndrome in which multiple CNS regions contribute to both the neurological and behavioural components (Costa-Mattioli and Monteggia, 2013; Han and Sahin, 2011; Jeste et al, 2008; Smalley, 1998)
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