Cubero, R. J. | bioRxiv Science

bioRxiv2021

A microRNA program controls the transition of cardiomyocyte hyperplasia to hypertrophy and stimulates mammalian cardiac regeneration

Myocardial regeneration is restricted to early postnatal life, when mammalian cardiomyocytes still retain the ability to proliferate. The molecular cues that induce cell cycle arrest of neonatal cardiomyocytes towards terminally differentiated adult heart muscle cells remain obscure. Here we report that the miR-106b[~]25 cluster is higher expressed in the early postnatal myocardium and decreases in expression towards adulthood, especially under conditions of overload, and orchestrates the transition of cardiomyocyte hyperplasia towards cell cycle arrest and hypertrophy by virtue of its targetome. In line, gene delivery of miR-106b[~]25 to the mouse heart provokes cardiomyocyte proliferation by targeting a network of negative cell cycle regulators including E2f5, Cdkn1c, Ccne1 and Wee1. Conversely, gene-targeted miR-106b[~]25 null mice display spontaneous hypertrophic remodeling and exaggerated remodeling to overload by derepression of the prohypertrophic transcription factors Hand2 and Mef2d. Taking advantage of the regulatory function of miR-106b[~]25 on cardiomyocyte hyperplasia and hypertrophy, viral gene delivery of miR-106b[~]25 provokes nearly complete regeneration of the adult myocardium after ischemic injury. Our data demonstrate that exploitation of conserved molecular programs can enhance the regenerative capacity of the injured heart.

molecular biology↗

bioRxiv2019

Action representation in the mouse parieto-frontal network

The posterior parietal cortex (PPC), along with anatomically linked frontal areas, form a cortical network which mediates several functions that support goal-directed behavior, including sensorimotor transformations and decision making. In primates, this network also links performed and observed actions via mirror neurons, which fire both when an individual performs an action and when they observe the same action performed by a conspecific. Mirror neurons are thought to be important for social learning and imitation, but it is not known whether mirror-like neurons occur in similar networks in other species that can learn socially, such as rodents. We therefore imaged Ca2+ responses in large neural ensembles in PPC and secondary motor cortex (M2) while mice performed and observed several actions in pellet reaching and wheel running tasks. In all animals, we found spatially overlapping neural ensembles in PPC and M2 that robustly encoded a variety of naturalistic behaviors, and that subsets of cells could stably encode multiple actions. However, neural responses to the same set of observed actions were absent in both brain areas, and across animals. Statistical modeling analyses also showed that performed actions, especially those that were task-specific, outperformed observed actions in predicting neural responses. Overall, these findings show that performed and observed actions do not drive the same cells in the parieto-frontal network in mice, and suggest that sensorimotor mirroring in the mammalian cortex may have evolved more recently, and only in certain species.

neuroscience↗