Familial Dysautonomia (FD) is an autosomal recessive congenital neuropathy that is caused by a mutation in the inhibitor of kappa B kinase complex-associated protein gene (IKBKAP). While FD patients suffer from multiple neuropathies, a major debilitation that affects their quality of life is progressive blindness. In order to determine the requirement for Ikbkap in the developing and adult retina, we generated Ikbkap conditional knockout (CKO) mice using a TUBA1a promoter-Cre (Tα1-Cre). In the retina, Tα1-Cre expression is detected predominantly in retinal ganglion cells (RGCs). At six months, significant loss of RGCs had occurred in the CKO retinas, with the greatest loss in the temporal retina, which is the same spatial phenotype observed in FD, and also in Leber hereditary optic neuropathy and dominate optic atrophy. Interestingly, the melanopsin+ RGCs were resistant to degeneration. By nine months, signs of photoreceptor degeneration were observed, which later progressed to pan-retinal degeneration including RGC and photoreceptor loss, optic nerve thinning, Müller glial activation and disruption of layers. Together, we conclude that while Ikbkap is not required for normal development of RGCs, its loss causes a slow, progressive RGC degeneration most severely in the temporal retina, which is later followed by indirect photoreceptor loss and complete retinal disorganization. This mouse model of FD is not only useful for identifying the mechanisms mediating retinal degeneration but provides a model system in which to attempt to test therapeutics that may mitigate the loss of vision in FD patients.
Significance Statement: FD is classified as a Hereditary sensory and autonomic neuropathy (Type III). A classic hallmark of the disease is progressive blindness marked by retinal ganglion cell (RGC) loss and optic nerve atrophy. To investigate the consequences of Ikbkap loss in the retina, we generated Ikbkap CKO mice using TUBA1a-Cre. In the retina, TUBA1a-Cre is expressed primarily in RGCs, and Ikbkap disruption led to slow, progressive RGC degeneration which was subtype and region specific. This was later followed by indirect photoreceptor loss and complete retinal disorganization. Our data demonstrate that this is a powerful model system that faithfully recapitulates the phenotype and progression of the FD blindness, and can be used to investigate potential therapeutics to treat retinal degeneration in FD.
The authors declare no competing financial interests.
This work was supported by NIH F32 EY023498-01A1 (to YU) and NIH R01 NS086796 and the Dysautonomia Foundation (to FL and MES).