Abstract
BackgroundPAX6 is a homeodomain transcription factor that acts in a highly dosage-sensitive manner to regulate the development and function of the eyes, nose, central nervous system, gut, and endocrine pancreas. Several individual microRNAs (miRNA) have been implicated in regulating PAX6 in different cellular contexts, but a more general view of how they contribute to the fine-tuning and homeostasis of PAX6 is poorly understood.ResultsHere, a comprehensive analysis of the Pax6 3′ untranslated region was performed to map potential miRNA recognition elements and served as a backdrop for miRNA expression profiling experiments to identify potential cell/tissue-specific miRNA codes. Pax6 3’UTR pull-down studies identified a cohort of miRNA interactors in pancreatic αTC1–6 cells that, based on the spacing of their recognition sites in the Pax6 3’UTR, revealed 3 clusters where cooperative miRNA regulation may occur. Some of these interacting miRNAs have been implicated in α cell function but have not previously been linked to Pax6 function and may therefore represent novel PAX6 regulators.ConclusionsThese findings reveal a regulatory landscape upon which miRNAs may participate in the developmental control, fine-tuning and/or homeostasis of PAX6 levels.
Highlights
PAX6 is a homeodomain transcription factor that acts in a highly dosage-sensitive manner to regulate the development and function of the eyes, nose, central nervous system, gut, and endocrine pancreas
Given that some miRNA recognition element (MRE) are predicted to be targeted by multiple miRNAs, and some miRNAs are predicted to target multiple MREs within the Pax6 3′ untranslated region (3’UTR), we identified 47 candidate miRNAs of interest and 42 candidate MREs (Fig. 3a, Additional file 3: Table S2 listed as “Primary Candidate” under “Reason Selected”). 12 of these MREs are predicted to be targeted by multiple miRNAs and 25 of the identified miRNAs are predicted to target multiple MREs within the Pax6 3’UTR
As proper PAX6 function is highly sensitive to its dosage, miRNA post-transcriptional regulation is predicted to play an important role in maintaining correct PAX6 levels
Summary
PAX6 is a homeodomain transcription factor that acts in a highly dosage-sensitive manner to regulate the development and function of the eyes, nose, central nervous system, gut, and endocrine pancreas. Pax overexpression in mice carrying multiple copies of the human PAX6 gene impairs normal development of the eye, leading to reduced eye size and photoreceptor loss in the retina [23] and causes cell autonomous defects in late cortical progenitor proliferation, resulting in decreased thickness of superficial cortical layers [24]. Transgenic mice overexpressing Pax during early pancreas development display perturbed development of the endocrine pancreas, Ryan et al BMC Genomics (2018) 19:820 β-cell apoptosis, and impaired glucose stimulated insulin secretion [25]. The physiological mechanism(s) regulating precise PAX6 expression levels have not been elucidated
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