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Lozano-Velasco, E.

Publications and source records attributed to Lozano-Velasco, E..

2 recordsLinked to original sources

The Pax6 master control gene initiates spontaneous retinal development via a self-organising Turing network

Understanding how complex organ systems are assembled from simple embryonic tissues is a major challenge. Across the animal kingdom a great diversity of visual organs are initiated by a master control gene called Pax6, which is both necessary and sufficient for eye development1-6. Yet precisely how Pax6 achieves this deeply homologous function is poorly understood. Here we show that vertebrate Pax6 interacts with a pair of morphogen-coding genes, Tgfb2 and Fst, to form a putative Turing network7, which we have computationally modelled. Computer simulations suggest that this gene network is sufficient to spontaneously polarise the developing retina, establishing the eyes first organisational axis and prefiguring its further development. Our findings reveal how retinal self-organisation may be initiated independent of the highly ordered tissue interactions that help to assemble the eye in vivo. These results help to explain how stem cell aggregates spontaneously self-organise into functional eye-cups in vitro8. We anticipate these findings will help to underpin retinal organoid technology, which holds much promise as a platform for disease modelling, drug development and regenerative therapies.

developmental biology↗

Ventricular chamber-specific Pitx2 insufficiency leads to cardiac hypertrophy and arrhythmias

Genome-wide association studies (GWAS) have identified genetic risk variant adjacent to the homeobox transcription factor PITX2 in atrial fibrillation (AF) patients. Experimental studies demonstrated that Pitx2 insufficiency leads to cellular and molecular substrates that increased atrial arrhythmias susceptibility. Pitx2 expression is present not only in the atrial but also in the ventricular myocytes. This study aims to investigate if insufficiency of Pitx2 in the developing and adult ventricular chambers increased susceptibility to ventricular arrhythmias. Conditional Pitx2 loss-offunction ventricular chamber-specific (Mlc2v-Cre) mouse mutants were generated using Cre/loxP technology. Pitx2 insufficiency in the ventricular myocardium leads interventricular septal thickening during cardiogenesis but else mice are viable until adulthood. Adult Mlc2vCre+Pitx2-/- hearts display hypertrophic and dilated ventricular chambers. ECG recordings demonstrated that Mlc2vCre+Pitx2-/- mice display increased QT and QRS intervals. Molecular analyses demonstrate that repolarization but not depolarization is severely impaired in these mutants. Microarrays analysis identified mRNAs and microRNAs altered in Pitx2 ventricular-specific mutants and provide evidences for miR-1 and miR-148 deregulation which in turn modulate Klf4 and distinct ion channel expression linked to cardiac hypertrophy and long QT-like defects. Our data demonstrate that Pitx2 insufficiency play leads to cellular and molecular ventricular remodeling which results in hypertrophic and dilated ventricular chambers and electrophysiological defects resembling long QT syndrome.

developmental biology↗