Tnks1bp1 a novel key player in the maintenance of hair cell progenitors.
Loss of hair cells (HC), the mechanoreceptors of sensory epithelia of the inner ear, is the major cause of non-syndromic hearing disorders. These sophisticated cells are highly sensitive to several otoxic factors including antibiotics, noise or simply ageing because we are born with a finite stock of them. Unlike mammals, lower vertebrates regenerate very efficiently those mechanoreceptors throughout their lifetime. In amphibians and fish, HC are also found in a skin deep sensory organ system, called the lateral line (LL). Organization, physiology, structure, ultra-structure and even gene expression in the LL and sensory epithelia of the inner ear are highly comparable. The LL is constituted of stereotypically distributed sensory patches called neuromasts (N). When HC in the N are destroyed, surrounding support cells (SC) dedifferentiate and a subset of them actively divide and give rise to new HC and SC therefore constituting a steady pool of HC progenitors. Regulation of SC proliferation has been described as controlled by canonical Wnt-signaling mostly based on chemical manipulation. No direct genetic evidence has been provided yet, most probably because of Wnt-signaling involvement in several crucial developmental events rendering mutations in any players of the pathway early lethal. We have previously described a novel and uncharacterized gene which expression we have trapped in a stable transgenic zebrafish line. We showed that it was strictly restricted to SC of the LL and of the olfactory epithelium, another regenerating structure. The cloned sequence revealed a highly-conserved signature domain, the tankyrase 1 binding domain, which lead us to postulate that this gene was a putative homolog of Tankyrase 1 binding protein 1(Tnks1bp1). In cell culture, tankyrase 1 (TNKS1) had been implicated in telomeres length maintenance and mitosis regulation providing a tantalizing mechanistic link. More recently TNKS1 has been described as a new partner of the Wnt-canonical signaling pathway rendering the involvement of tnks1bp1 in HC regeneration even more probable. Using CRISPR-Cas genome editing technology, we generated several null alleles which we started to analyze. The overall development of the LL in tnks1bp1 homozygotes (tnks1bp1-/-) seems unaffected, but as early as 5day post fertilization (dpf) all N have strikingly less HC and SC, which strongly suggests that tnks1pb1 is crucial in maintenance of the HC progenitor pool.
Department of Anatomy and Neurobiology, San Juan, University of Puerto Rico
Domain 2 - UMR 3215 / U934 - Genetics and Developmental Biology