Maturation arrest in early postnatal sensory receptors by deletion of the miR-183/96/182 cluster in mouse

Abstract

The polycistronic miR-183/96/182 cluster is preferentially and abundantly expressed in terminally differentiating sensory epithelia. To clarify its roles in the terminal differentiation of sensory receptors in vivo, we deleted the entire gene cluster in mouse germline through homologous recombination. The miR-183/96/ 182 null mice display impairment of the visual, auditory, vestibular, and olfactory systems, attributable to profound defects in sensory receptor terminal differentiation. Maturation of sensory receptor precursors is delayed, and they never attain a fully differentiated state. In the retina, delay in up-regulation of key photoreceptor genes underlies delayed outer segment elongation and possibly mispositioning of cone nuclei in the retina. Incomplete maturation of photoreceptors is followed shortly afterward by early-onset degeneration. Cell biologic and transcriptome analyses implicate dysregulation of ciliogenesis, nuclear translocation, and an epigenetic mechanism that may control timing of terminal differentiation in developing photoreceptors. In both the organ of Corti and the vestibular organ, impaired terminal differentiation manifests as immature stereocilia and kinocilia on the apical surface of hair cells. Our study thus establishes a dedicated role of the miR-183/96/182 cluster in driving the terminal differentiation of multiple sensory receptor cells. M ammalian sensory epithelia, such as those underlying vison, hearing, smell, and balance, consist of ciliated sensory receptor cells. Although highly specialized, similarities in embryonic origin underlie common features in their development (1). Following specification, lineage-restricted postmitotic precursors become structurally and functionally mature through a series of cellular differentiation events, collectively described as terminal differentiation (2). During maturation, sensory receptor cells typically develop microtubule-based primary cilia and in some cases actin-based membrane protrusions on apical membranes, which are sensory organelles, while maintaining apical basal polarity within sensory epithelia. In photoreceptors, for example, the extension of outer segments (OSs), specialized sensory cilia, is central to postmitotic differentiation and necessary for light sensitivity (3). In auditory and vestibular hair cells, the proper formation of hair bundles is indispensable for detecting sound and head positions (4). Similarly, olfactory sensory neurons (OSNs), the odorant receptor cells in the olfactory epithelium, project multiple dendritic cilia into the mucous membrane of the nasal epithelium where olfactory signaling is initiated (5). Mature sensory epithelia are highly structured with specific spatial organization that is tied to their functions. Synchronized planar cell polarity (PCP) of hair cells in the inner ear, for example, provides their directional sensitivity (6), whereas the development of laminar architecture in the retina restricts photoreceptors to proper compartments for efficient wiring with secondary neuro...

Functional microRNA targetome undergoes degeneration-induced shift in the retina

“…Expectedly, AGO2-loaded miRNA found in both DR and PD groups, comprised miRNAs that are known to play a role in retinal development and homeostasis such as the photoreceptor cluster miR-183/96/182 (Bellon et al, 2017, Busskamp et al, 2014, Fan et al, 2017, Karali et al, 2007, Krol et al, 2010, Lumayag et al, 2013, Xiang et al, 2017, Xu et al, 2007; miR-204-5p (Barbato et al, 2017, Conte et al, 2010, Conte et al, 2015, Karali et al, 2016, let-7a-5p (La Torre et al, 2013) and miR-124-3p (Chu-Tan et al, 2018, Karali et al, 2007, Sanuki et al, 2011, showing consistent overlap with previous studies. However, despite significant changes in differential global miRNA expression in the damaged retina, there were no significant changes in AGO2-loaded miRNA between DR and PD retinas suggesting that the retina appears to be utilising the existing miRNA population in both physiological states.…”

Characterising the Transcriptional and Translational Impact of the Schizophrenia-Associated miR-1271-5p in Neuronal Cells

“…We can make some further assumptions about the role of miR-1271-5p in the brain by looking at the activity of its seed pairing homolog miR-96-5p, as it is likely they have similar targets and regulatory activity [15]. For example, miR-96-5p expression has been associated with the coordination of neural crest [49] and auditory hindbrain development [50], as well as the induction and progression of neuronal differentiation [51][52][53]. It has also been shown to be involved in the regulation of long-term memory [54,55] and pain sensitivity [56].…”

The miR-183/96/182 Cluster Regulates Macrophage Functions in Response to <b><i>Pseudomonas aeruginosa</i></b>

“…It was originally identified as a sensory organ-specific miRNA cluster [7, 8]. We and others have shown that miR-183/96/182 is required for the normal function of all major sensory organs, including vision [8], hearing and balance [8-10], olfaction [11], and pain [12]. Recently, mounting evidence from our group and others demonstrated that member(s) of miR-183/96/182 are also expressed and play important roles in both innate [13-16] and adaptive immune systems [17-19], suggesting that miR-183/96/182 provides one of the first shared genetic links between the immune and traditional sensory systems, supporting the recently emerging concept of the immune system as a sensory system [20].…”