Roles of planar cell polarity pathways in the development of neutral tube defects

Wu et al. Journal of Biomedical Science 2011, 18:66 http://www.jbiomedsci.com/content/18/1/66 REVIEW Open Access Roles of planar cell polarity pathways in the development of neutral tube defects Gang Wu1,2, Xupei Huang2, Yimin Hua1 and Dezhi Mu1,3* Abstract Neural tube defects (NTDs) are the second most common birth defect in humans. Despite many advances in the understanding of NTDs and the identification of many genes related to NTDs, the fundamental etiology for the majority of cases of NTDs remains unclear. Planar cell polarity (PCP) signaling pathway, which is important for polarized cell movement (such as cell migration) and organ morphogenesis through the activation of cytoskeletal pathways, has been shown to play multiple roles during neural tube closure. The disrupted function of PCP pathway is connected with some NTDs. Here, we summarize our current understanding of how PCP factors affect the pathogenesis of NTDs. Keywords: Neural tube defects, planar cell polarity, organ morphogenesis, signaling pathway Background Neural tube defects (NTDs), arise when the neural tube, the embryonic precursor of the brain and spinal cord, fails to close during neurulation. Defects in neural tube closure are the second most common human birth defects, after congenital heart defects [1]. Recent birth prevalence estimates show that NTDs account for 0.5 per 1000 in the United States during 2001-2004, 1 to 1.5 per 1000 in Western Australia during 2001-2006, and 2.8 per 1000 in Iran during 1998-2005, while prevalence in Shanxi, a province in North China, reach to 19.9 per 1000 during 2002-2004 [2]. The cranial region (anencephaly) or the low spine (open spina bifida and myelomeningocele) are most commonly affected [3]. NTDs affecting the brain are invariably lethal perinatally, whereas open spina bifida is compatible with postnatal survival but frequently results in serious handicap, because neurological impairment below the lesion leads to lack of sensation, inability to walk and incontinence [4]. Neural tube formation and NTDs classification Neural tube closure is the result of neurulation, a process in which the neural plate bends upwards and * Correspondence: 1 Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China Full list of author information is available at the end of the article eventually fuses to form the hollow tube that will become the brain and the spinal cord. The driving force of neural tube closure is provided and maintained by cells undergoing convergence and extension (CE) [5]. Both fish (such as zebrafish) and amphibian (such as Xenopus) embryos require this process [6,7]. Neurulation is conserved between mammalian species [8] and can be conventionally divided into primary and secondary phases [9]. In primary neurulation, the fusion occurs along the spine and culminates in final closure at the posterior neuropore. Closure is initiated at the hindbrain/cervical boundary (Closure 1) and then spreads bi-directionally into the hindbrain and along the spinal region. Separate closure initiation sites occur at the midbrain-forebrain boundary (Closure 2) and at the rostral extremity of the forebrain (Closure 3). However, Closure 2 found in mice may be absent from human neurulation [10]. The secondary phase occurs at lower sacral and caudal levels, where the neural tube is formed in the tail bud without neural folding [4,11]. Failure of Closure 1 leads to the most severe NTD, craniorachischisis, which combines an open neural tube encompassing the midbrain, hindbrain and entire spinal region. If Closure 1 is completed but closure of the cranial neural tube is incomplete, anencephaly develops, with cases exhibiting either defects confining in the midbrain (meroanencephaly) or lesions extending into © 2011 Wu et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Wu et al. Journal of Biomedical Science 2011, 18:66 http://www.jbiomedsci.com/content/18/1/66 the hindbrain (holoanencephaly) [12]. Failure of Closure 3 is uncommon but, when present, yields split face with anencephaly. In the spinal region, failure of final closure at the posterior neuropore yields open spina bifida (also called myelocele or myelomeningocele), in which the upper limit can be of varying axial level [9]. By contrast, defective secondary neurulation leads to ‘closed’ forms of spina bifida [9]. Page 2 of 10 imbalance of 16q12.1-q22.1 is also associated with spina bifida in the patient [36]. Recently, a major advance in understanding of the genetic basis of neurulation is the finding that the initiation of Closure 1 requires noncanonical Wnt signaling, the so-called planar cell polarity (PCP) signaling pathway [3]. PCP signaling pathway Human NTDs and possible causes Epidemiological studies provide an opportunity to identify risk factors for NTDs, such as dietary or teratogenic agents, to which susceptibility may be modified by genetic predisposition [3,13,14]. Identification of causative factors is confounded by the fact that the majority of these malformations appears to result from a combination of genetic and non-genetic factors (environmental contributions) [3]. Many non-genetic factors may be associated with NTDs formation. They include: parental socioeconomic status [15,16], parental age [17], parental race [18], hyperthermia during early pregnancy [19], maternal health (such as diabetes [20], obesity [21]), dietary agents or maternal nutrition (such as the uptake of folate [22-24], inositol [25,26]), chemical teratogenic agents (such as valproic acid [27], retinoic acid [28], trichostatin A [29], exposure to pesticides [30] and selective serotonin-reuptake inhibitors [31] and so on). As for genetic factors, the cumulative number of reported mouse genetic mutants with NTDs continues to rise steadily, from approximately 200 in 2007 [32] to approximately 245 in 2010 [33]. The different mouse gene mutations, naturally occurring or targeted mutations, are associated with various NTD phenotypes [3,9,32]. Many of the NTD-causing mouse mutations implicate specific signaling pathways such as PCP signaling, Sonic hedgehog (Shh) signaling, BMP signaling, Notch signaling, retinoid signaling and inositol metabolism [4]. Those signaling pathways are involved in the maintenance of the cell cycle, the regulation of the actin cytoskeleton, chromatin organization and epigenetic modifications including methylation and acetylation [3]. However, although there is evidence for a strong genetic component in the individual liability to NTDs in humans, little is known about the nature of these risk genes about their interactions with each other. In general, the risk genes are present in the (...truncated)