MicroRNA targeting of the non‐canonical planar cell polarity pathway in the developing neural tube

Abstract

MicroRNAs (miRNAs) provide context-dependent transcriptional regulation of genes comprising signalling networks throughout the developing organism including morphogenesis of the embryonic neural tube (NT). Using a high-sensitivity, high-coverage microarray analysis platform, miRNA expression in the murine embryonic NT during the critical stages of its formation was examined. Analysis of a number of differentially expressed (DE) miRNAs enabled identification of several gene targets associated with cellular processes essential for normal NT development. Using computational pathway analysis, interactive biologic networks and functional relationships connecting DE miRNAs with their targeted messenger RNAs (mRNAs) were identified. Potential mRNA targets and a key signal transduction pathway governing critical cellular processes indispensable for normal mammalian neurulation were also identified. RNA preparations were also used to hybridize both miRNA arrays and mRNA arrays allowing miRNA-mRNA target analysis using data of DE miRNAs and DE mRNAsco-expressed in the same developing NT tissue samples. Identification of these miRNA targets provides key insight into the epigenetic regulation of NT development as well as into potential mechanistic underpinning of NT defects. Significance of the study: This study underscores the premise that microRNAs are potential coordinators of normal neural tube (NT) formation, via regulation of the crucial, planar cell polarity pathway. Any alteration in their expression during neurulation would result in abnormal NT development. K E Y W O R D S development, embryo, miRNA, neural tube, planar cell polarity pathway 1 | INTRODUCTION Neurulation is a central event in early mammalian development during which the neural plate and, subsequently, the neural tube (NT) are transformed into the primitive structures that will ultimately develop into the brain and spinal cord. Mammalian neurulation involves elevation of the neural folds from a horizontal neural plate, followed by their apposition and fusion. Fusion of the neural folds commences at four discrete closure points and extends in rostral and caudal directions along the embryonic central axis. 1 Aberrant or failed closure of the NT during the first trimester of human pregnancy leads to a range of NT defects (NTDs) of varying severity affecting the brain and spinal cord. These include anencephaly, craniorachischisis, spina bifida and encephalocele. 2 NTDs are among the most common human malformations, with an overall global incidence of approximately 0.5-2.0 per 1000 live births. 3 The aetiology of NTDs is multifactorial,

Single nucleotide polymorphisms of PCP pathway related genes participate in the occurrence and development of neural tube defect

“…The role of Wnt/PCP pathway in vertebrate cell movement during embryogenesis was first found in Xenopus and zebrafish (Heisenberg et al, 2000; Wallingford et al, 2000). During neurulation, when the neuraxis is elongated and eventually neural tube is closed, the convergent extension of the mid region of the neural plate occurs (Mukhopadhyay et al, 2020; Wallingford et al, 2020) which is mediated by PCP pathway. The core genes Frizzled ( Fzd ) and VANGL of PCP pathway encode transmembrane proteins (Nikolopoulou et al, 2017).…”

Dysregulated expression of miR‑367 in disease development and its prospects as a therapeutic target and diagnostic biomarker (Review)

“…Precise control of NPC behaviors, such as proliferation, differentiation and survival, is essential for coordinating this process and preventing open neural tube defects (NTDs). miRNAs are ideal regulators for orchestrating these cellular behaviors for normal neural tube (NT) formation by binding to multiple targets that regulate the planar cell polarity pathway (70). A mouse development study demonstrated that miR-302/367 expression started in the embryonic region after implantation and became restricted to the anterior neural tube by embryonic day 8.5 (55).…”

Up-regulation of miR-10a-5p expression inhibits the proliferation and differentiation of neural stem cells by targeting <italic>Chl1</italic>

“…The nervous system is enriched in miRNAs, which play important roles in neural development [15][16][17][18]. The possible mechanism underlying the effectiveness of environmental risk factors in NTDs was recently explored via miRNA expression using low-or highdensity microarrays [19][20][21][22][23], including reports of the abnormal expression of miRNAs in NTDs. In particular, several studies have reported that miRNA expression dysregulation contributes to the mechanism of RA-induced NTDs [24,25].…”