We thank Kirklin Maclise for assistance in quantifying neuromasts

We thank Kirklin Maclise for assistance in quantifying neuromasts. formation, further implicating a role for prion protein in cell adhesion. Introduction Prion protein, PrPC, is usually a conserved GPI-anchored protein that can undergo conformational changes to a ?-sheet enriched form called PrPSc, which is usually involved in the etiology of transmissible spongiform encephalopathy (TSE). The misfolded form PrPSc is well known for its ability to recruit and template the misfolding of normal cellular PrPC, initiating the pathological development of the disease and TSE [1]C[3]. Furthermore, increasing data demonstrate the involvement of PrPC in mediating A? oligomer toxicity in Alzheimer’s disease models [4], [5]. A? oligomers affect the localization of PrPC at LY2811376 the cell surface through a high affinity interaction. In addition, lack of PrPC rescues memory impairment and loss of synaptic markers [1], [5], [6], [7]. Moreover prion and amyloid precursor protein have a conserved conversation, exhibited functionally in zebrafish and at the biochemical level in humans [8]. PrPC is involved in many cellular processes such as neuritic outgrowth [9], adhesion and neuronal activity [1]. PrPC disruption prospects to an increased sensitivity to toxins or hypoxia that results in neuronal death, reflecting a neuroprotective role for PrPC [10], [11]. Mouse knockout models for the prion gene display normal development, metabolism LY2811376 and lifespan, and present with a resistance to PrPSc contamination [12], [13]. In the zebrafish model, the gene is usually duplicated and the expression of the two paralagous genes and are dissociated both spatially and temporally: (i) PrP1 is usually expressed during early embryonic stages in the whole embryo and is down regulated before the pharyngula LY2811376 stage [14]; and (ii) LY2811376 PrP2 expression coincides with the onset of somitogenesis and is expressed in the central nervous system and cranial ganglia. In comparison with the mammalian gene, represents the closest ortholog [15]. While mouse gene knockout does not impact any major developmental or physiological process, inactivation in zebrafish results in a dramatic phenotype with cellular movement defects and early embryonic lethality [8], [14], [16]. Such severe phenotypes have been linked to the loss of blastomere cell adhesion and in particular to the decreased stability of adherens junctions. inactivation prospects to nervous system malformations that affect the anterior part of the neural tube, essentially the Mouse monoclonal to KDR telencephalic, midbrain and hindbrain regions [14], [17]. However, discrepancies have been observed following gene inactivation using gene targeting, as mutant embryos or larvae show no developmental abnormalities but impaired NMDA receptor regulation [18]. Whether the gene is required in nervous system development is LY2811376 still in argument and morpholino-mediated inactivation has to be cautiously evaluated. To clarify the role of PrP2, we required advantage of the well-characterized mechano-sensory system, the zebrafish posterior lateral collection (PLL). The PLL ganglion displays a strong expression of PrP2 as early as 30 hours post-fertilization (hpf) and at later developmental stages mRNA is observed in the differentiated sensory organs, including in the neuromasts and in its differentiated hair cells [14], [19]. The PLL provides a powerful model to study multiple cellular processes such as cell migration, axonal outgrowth and differentiation process. PLL development relies on the migration of the primordium, a cohesive group of cells that is organized and polarized throughout the migration process. Sensory organs called neuromasts are organized in a stereotype pattern along the PLL at the body surface. Hair cells situated at the center of each neuromast register and measure water movements and are homologs of mammalian inner ear hair cells [20]. In the present study, using morpholino knockdown, we performed partial gene inactivation and exhibited that PrP2 is required for the development of the PLL. Transient inactivation of gene induced abnormal neuromast deposition, as well as defects in the PLL nerve trajectories. Comparison with loss of function mutant confirmed abnormal neuromast positioning and partial disorganization of the primordium. Furthermore, analysis of the primordium development revealed an abnormal.