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A model for reticular dysgenesis shows impaired sensory organ development and hair cell regeneration linked to cellular stress.

Disease models & mechanisms (2019-11-16)
Alberto Rissone, Erin Jimenez, Kevin Bishop, Blake Carrington, Claire Slevin, Stephen M Wincovitch, Raman Sood, Fabio Candotti, Shawn M Burgess
ABSTRACT

Mutations in the gene AK2 are responsible for reticular dysgenesis (RD), a rare and severe form of primary immunodeficiency in children. RD patients have a severely shortened life expectancy and without treatment die, generally from sepsis soon after birth. The only available therapeutic option for RD is hematopoietic stem cell transplantation (HSCT). To gain insight into the pathophysiology of RD, we previously created zebrafish models for Ak2 deficiencies. One of the clinical features of RD is hearing loss, but its pathophysiology and causes have not been determined. In adult mammals, sensory hair cells of the inner ear do not regenerate; however, their regeneration has been observed in several non-mammalian vertebrates, including zebrafish. Therefore, we used our RD zebrafish models to determine whether Ak2 deficiency affects sensory organ development and/or hair cell regeneration. Our studies indicated that Ak2 is required for the correct development, survival and regeneration of sensory hair cells. Interestingly, Ak2 deficiency induces the expression of several oxidative stress markers and it triggers an increased level of cell death in the hair cells. Finally, we show that glutathione treatment can partially rescue hair cell development in the sensory organs in our RD models, pointing to the potential use of antioxidants as a therapeutic treatment supplementing HSCT to prevent or ameliorate sensorineural hearing deficits in RD patients.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Dimethyl sulfoxide, Hybri-Max, sterile-filtered, BioReagent, suitable for hybridoma, ≥99.7%
Sigma-Aldrich
L-Glutathione reduced, ≥98.0%
Sigma-Aldrich
Copper(II) sulfate, anhydrous, powder, ≥99.99% trace metals basis
Supelco
Ethyl 3-aminobenzoate methanesulfonate salt, analytical standard
Sigma-Aldrich
N-Phenylthiourea, ≥98%
Sigma-Aldrich
Nuclear Fast Red solution
Sigma-Aldrich
BIO, ≥98% (HPLC)
Sigma-Aldrich
AG 1478 - CAS 175178-82-2 - Calbiochem, A cell-permeable, reversible, ATP-competitive, highly potent and selective inhibitor of epidermal growth factor receptor kinase versus HER2-neu and platelet-derived growth factor receptor kinase.
Sigma-Aldrich
5-Propyl-2-thiouracil, ≥98%