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Neural crest migration is critical to its physiological function. Mechanisms controlling mammalian neural crest migration are comparatively unknown, due to difficulties accessing this cell population in vivo. Here we report requirements of glycogen synthase kinase 3 (GSK3) in regulating the neural crest in Xenopus and mouse models. We demonstrate that GSK3 is tyrosine phosphorylated (pY) in mouse neural crest cells and that loss of GSK3 leads to increased pFAK and misregulation of Rac1 and lamellipodin, key regulators of cell migration. Genetic reduction of GSK3 results in failure of migration. We find that pY-GSK3 phosphorylation depends on anaplastic lymphoma kinase (ALK), a protein associated with neuroblastoma. Consistent with this, neuroblastoma cells with increased ALK activity express high levels of pY-GSK3, and blockade of GSK3 or ALK can affect migration of these cells. Altogether, this work identifies a role for GSK3 in cell migration during neural crest development and cancer. Defects in neural crest development cause neurocristopathies and cancer, but what regulates this is unclear. Here, the authors show that glycogen synthase kinase 3 (GSK3) regulates migration of neural crest cells, as shown on genetic deletion of GSK3 in the mouse, and that this acts via anaplastic lymphoma kinase.

Craniosynostosis is a birth defect occurring in approximately one in 2000 live births, where premature fusion of the cranial bones inhibits growth of the skull during critical periods of brain development. The resulting changes in skull shape can lead to compression of the brain, causing severe complications. While we have some understanding of the molecular pathology of craniosynostosis, a large proportion of cases are of unknown genetic aetiology. Based on studies in mouse, we previously proposed that the ciliopathy gene Fuz should be considered a candidate craniosynostosis gene. Here, we report a novel variant of FUZ (c.851 G > C, p.(Arg284Pro)) found in monozygotic twins presenting with craniosynostosis. To investigate whether Fuz has a direct role in regulating osteogenic fate and mineralisation, we cultured primary osteoblasts and mouse embryonic fibroblasts (MEFs) from Fuz mutant mice. Loss of Fuz resulted in increased osteoblastic mineralisation. This suggests that FUZ protein normally acts as a negative regulator of osteogenesis. We then used Fuz mutant MEFs, which lose functional primary cilia, to test whether the FUZ p.(Arg284Pro) variant could restore FUZ function during ciliogenesis. We found that expression of the FUZ p.(Arg284Pro) variant was sufficient to partially restore cilia numbers, but did not mediate a comparable response to Hedgehog pathway activation. Together, this suggests the osteogenic effects of FUZ p.(Arg284Pro) do not depend upon initiation of ciliogenesis.

BACKGROUNDS: Nasoalveolar molding (NAM) application is among presurgical management (PSM) techniques used for infants with cleft lip and palate (CLP). It helps to approximate the palatal cleft and to reshape the nasoalveolar complex prior to primary lip repair. This study aimed to explore types of PSM and the dental speciality provision for infants with CLP in Baghdad. The status of NAM usage and surgeons' perceptions toward NAM usage were assessed. MATERIALS AND METHODS: This is a cross-sectional paper-based questionnaire study that collected responses of surgeons perform primary lip and nose repair regarding PSM. The questionnaire was distributed amongst public and private hospitals in Baghdad. Twenty surgeons were enrolled (only those surgeons who perform primary repair for infants with CLP); two females and eighteen males. RESULTS: The majority of participants' responses suggested that the majority of infants with CLP were provided with baby feeding plates and lip straps. Six surgeons reported that a percentage of their patients who have been provided with NAM. PSM in Baghdad was mostly supplied by orthodontists and plastic surgeons, and the next most likely providers were prosthodontists. 82.35% of the surgeons found that primary surgical repair procedures were easier with NAM than for the other infants. The rest have not perceived any differences. CONCLUSIONS: Orthodontists, surgeons and prosthodontists were involved in providing PSM. Baby feeding plates and lip straps were the most common PSM in Baghdad, although NAM is not uncommon. Most surgeons believe that using NAM made surgical procedures easier and permitted the prediction of surgical outcomes.

John Wallingford and colleagues combine proteomics, in vivo imaging and genetic analyses to identify a new ciliopathy-associated protein module, which they call CPLANE. They show that CPLANE proteins, which include Fuzzy, Inturned and Wdpcp, interact with Jbts17 at basal bodies, where they act to recruit a specific subset of intraflagellar transport proteins. Cilia use microtubule-based intraflagellar transport (IFT) to organize intercellular signaling. Ciliopathies are a spectrum of human diseases resulting from defects in cilia structure or function. The mechanisms regulating the assembly of ciliary multiprotein complexes and the transport of these complexes to the base of cilia remain largely unknown. Combining proteomics, in vivo imaging and genetic analysis of proteins linked to planar cell polarity (Inturned, Fuzzy and Wdpcp), we identified and characterized a new genetic module, which we term CPLANE (ciliogenesis and planar polarity effector), and an extensive associated protein network. CPLANE proteins physically and functionally interact with the poorly understood ciliopathy-associated protein Jbts17 at basal bodies, where they act to recruit a specific subset of IFT-A proteins. In the absence of CPLANE, defective IFT-A particles enter the axoneme and IFT-B trafficking is severely perturbed. Accordingly, mutation of CPLANE genes elicits specific ciliopathy phenotypes in mouse models and is associated with ciliopathies in human patients.

Acoustic communication is fundamental to social interactions among animals, including humans. In fact, deficits in voice impair the quality of life for a large and diverse population of patients. Understanding the molecular genetic mechanisms of development and function in the vocal apparatus is thus an important challenge with relevance both to the basic biology of animal communication and to biomedicine. However, surprisingly little is known about the developmental biology of the mammalian larynx. Here, we used genetic fate mapping to chart the embryological origins of the tissues in the mouse larynx, and we describe the developmental etiology of laryngeal defects in mice with disruptions in cilia-mediated Hedgehog signaling. In addition, we show that mild laryngeal defects correlate with changes in the acoustic structure of vocalizations. Together, these data provide key new insights into the molecular genetics of form and function in the mammalian vocal apparatus. Nearly all animals communicate using sound. In many cases these sounds are in the form of a voice, which in mammals is generated by a specialized organ in the throat called the larynx. Millions of people throughout the world have voice defects that make it difficult for them to communicate. Such defects are distinct from speech defects such as stuttering, and instead result from an inability to control the pitch or volume of the voice. This has a huge impact because our voice is so central to our quality of life. A wide range of human birth defects that are caused by genetic mutations are known to result in voice problems. These include disorders in which the Hedgehog signaling pathway, which allows cells to exchange information, is defective. Projections called cilia that are found on the outside of many cells transmit Hedgehog signals, and birth defects that affect the cilia (called ciliopathies) also often result in voice problems. Although the shape of the larynx has a crucial effect on voice, relatively little is known about how it develops in embryos. Mice are often studied to investigate how human embryos develop. By studying mouse embryos that had genetic mutations similar to those seen in humans with ciliopathies, Tabler, Rigney et al. now show that many different tissues interact in complex ways to form the larynx. A specific group of cells known as the neural crest was particularly important. The neural crest helps to form the face and skull and an excess of these cells causes face and skull defects in individuals with ciliopathies. Tabler, Rigney et al. show that having too many neural crest cells can also contribute towards defects in the larynx of mice with ciliopathies, despite the larynx being in the neck. Further investigation showed that the Hedgehog signaling pathway was required for the larynx to develop properly. Furthermore, recordings of the vocalizations of the mutant mice showed that they had defective voices, thus linking the defects in the shape of the larynx with changes in the vocalizations that the mice made. Overall, Tabler, Rigney et al. show that mice can be used to investigate how the genes that control the shape of the larynx affect the voice. The next step will be to use mice to investigate other genetic defects that cause voice defects in humans. Further research in other animals could also help us to understand how the larynx has evolved.

Orthodontically induced inflammatory root resorption (OIIRR) is an undesirable complication of orthodontic treatment (OT) with an ambiguous aetiologic mechanism. This study aimed to identify OIIRR-associated biomarkers in the gingival crevicular fluid (GCF) using proteomic analysis. In this randomized clinical trial, the upper first premolars (UFP) were exposed either to light or heavy force. The GCF was collected at 1 h, 1 day, 7 days, 14 days, 21 days, and 28 days following force application. After extraction of UFP, roots were imaged and resorption premolar, was used to deliver either light forcecraters were measured. Proteomic analysis of GCF was performed using 2D gel electrophoresis with MALDI-TOF/TOF MS/MS. Results were further analyzed by bioinformatics analyses showing the biological functions and predicted pathways. The predicted canonical pathways showed that the expression of immunoglobulin kappa (IGKC), neutrophil gelatinase-associated lipocalin (NGAL), neurolysin mitochondrial (NEUL), keratin, type II cytoskeletal 1 (K2C1), S100-A9, and the extracellular calcium-sensing receptor (CASR) were significantly associated with a range of biological and inflammatory processes. In conclusion, up-regulation of S100A9, CASR, and K2C1 suggested a response to force-related inflammation, chemotactic activities, osteoclastogenesis, and epithelial cell breakdown. Meanwhile, the up-regulation of IGKC, NGAL, and K2C1 indicated a response to the inflammatory process, innate immunity activation, and epithelial cell breakdown.

The tongue is a highly specialized muscular organ important for breathing, speech, taste and swallowing. The secreted signaling molecule Sonic hedgehog (Shh) is expressed in dorsal tongue epithelium from the initial developmental stage. In this study, we utilized a series of genetic approaches to investigate the role of Shh during mouse tongue formation. Temporal-specific global deletion of Shh demonstrated a functional requirement for normal patterning of the intrinsic tongue muscles and establishment of the lingual tendon. These defects were reproduced in the mutant with a specific loss of signaling in oropharyngeal epithelium by a Shh cis-enhancer. In these mutants, Ptch1 was lost in the underlying cranial neural crest (CNC)-derived mesenchymal lineage. The importance of Shh was confirmed by generating tissue-specific deletions in the ciliopathy gene Ofd1, which transduces Shh signaling. These results revealed Shh roles in patterning of the mesodermal intrinsic tongue muscles through CNC-derived mesenchyme, including the lingual tendon.

Nat. Genet. 48, 648–656 (2016); published online 9 May 2016; corrected after print 30 May 2016 In the version of this article initially published, the name of author Daniela A. Braun was misspelled. The error has been corrected in the HTML and PDF versions of the article.