Diverse signaling cues and attendant proteins work together during organogenesis, including craniofacial development. Lip and palate formation starts as early as the fourth week of gestation in humans or embryonic day 9.5 in mice. Disruptions in these early events may cause serious consequences, such as orofacial clefts, mainly cleft lip and/or cleft palate. Morphogenetic Wnt signaling, along with other signaling pathways and transcription regulation mechanisms, plays crucial roles during embryonic development, yet the signaling mechanisms and interactions in lip and palate formation and fusion remain poorly understood. Various Wnt signaling and related genes have been associated with orofacial clefts. This Review discusses the role of Wnt signaling and its crosstalk with cell adhesion molecules, transcription factors, epigenetic regulators and other morphogenetic signaling pathways, including the Bmp, Fgf, Tgfβ, Shh and retinoic acid pathways, in orofacial clefts in humans and animal models, which may provide a better understanding of these disorders and could be applied towards prevention and treatments.

Background The development of an autistic brain is a highly complex process as evident from the involvement of various genetic and non-genetic factors in the etiology of the autism spectrum disorder (ASD). Despite being a multifactorial neurodevelopmental disorder, autistic patients display a few key characteristics, such as the impaired social interactions and elevated repetitive behaviors, suggesting the perturbation of specific neuronal circuits resulted from abnormal signaling pathways during brain development in ASD. A comprehensive review for autistic signaling mechanisms and interactions may provide a better understanding of ASD etiology and treatment. Main body Recent studies on genetic models and ASD patients with several different mutated genes revealed the dysregulation of several key signaling pathways, such as WNT, BMP, SHH, and retinoic acid (RA) signaling. Although no direct evidence of dysfunctional FGF or TGF-β signaling in ASD has been reported so far, a few examples of indirect evidence can be found. This review article summarizes how various genetic and non-genetic factors which have been reported contributing to ASD interact with WNT, BMP/TGF-β, SHH, FGF, and RA signaling pathways. The autism-associated gene ubiquitin-protein ligase E3A ( UBE3A ) has been reported to influence WNT, BMP, and RA signaling pathways, suggesting crosstalk between various signaling pathways during autistic brain development. Finally, the article comments on what further studies could be performed to gain deeper insights into the understanding of perturbed signaling pathways in the etiology of ASD. Conclusion The understanding of mechanisms behind various signaling pathways in the etiology of ASD may help to facilitate the identification of potential therapeutic targets and design of new treatment methods.

Introduction: Iron is an important factor in neural development. Iron Deficiency (ID) and Iron Deficiency Anaemia (IDA) anaemia is highly prevalent in patients of autism. There are a very small number of studies to show association between iron profile and autism. Aim: To investigate factors affecting iron status such as hemoglobin (%), serum iron, ferritin, and Total Iron Binding Capacity (TIBC) level in children with Autism Spectral Disorder (ASD) and healthy control. Materials and Methods: It was a case-control study done from April 2018 to April 2019. Total 100 participants were recruited of which 50 autistic patients were taken as cases, and 50 healthy subjects were taken as control. Childhood Autism Rating Scale (CARS) was used to evaluate the severity of autistic symptoms. Cut-off value of serum ferritin was <10 ng/mL for preschoolers (<6 years) and <12 ng/mL for school-aged (>6 years) children to evaluate ID. Anaemia was defined as haemoglobin <11.0 g/dL for preschoolers and <12.0 g/dL for school-aged categorical variables and were compared by using chi-square test. Normally distributed parametric variables were compared between groups by using independent samples t-test. Serum ferritin, iron, TIBC values were compared between severe, mild-moderate and control groups with ANOVA. The p-value <0.05 was accepted to be statistically significant. Results: Mean serum levels of ferritin iron TIBC were significantly reduced in ASD patients (p<0.001). The level of haemoglobin was also lower in ASD patients but it was not significant. Risk of ID and IDA was higher than normal subjects (RR for ID 1.74). Level of serum ferritin, iron and TIBC was lowest in severe autism as compared to mild-moderate autism and control groups. Conclusion: These findings suggest iron and ferritin levels should be measured in autistic patients as a baseline investigation and it may be used as a screening test for ASD.

Lombardi Comprehensive Cancer Center, and Department of Biochemistry and Molecular & Cellular Biology Georgetown University, Washington, DC 20057, USA. Heavy ion space radiation is considered as a risk factor of gastrointestinal (GI) cancer and perturbed intestinal epithelial cell (IEC) migration has been implicated in GI carcinogenesis. The purpose of the current study was to assess rate of IEC migration as well as dissect key IEC migration signaling events after exposure to heavy ion 56Fe irradiation and compare the results to sham- and γ-irradiation. Male C57BL/6J mice were exposed to 0.5 Gy of either γ or 56Fe radiation and control mice were sham irradiated. IEC migration distance was measured 7 and 60 d after exposure using BrdU pulse labeling. We also analyzed cell polarity, microtubule dynamics, and adhesion dynamics using immunoblots and immunofluorescence. Measure of IEC migration rate showed a greater decrease after 56Fe relative to γ radiation at both the time points. At the molecular level, compared to sham and γ radiation, 56Fe radiation exhibited significantly greater impairment of cell adhesion dynamics evidenced by altered integrins and Rock1 as well as cytoskeletal dynamics evidenced by altered MLCK expression. Similarly, perturbed cell polarity, tight junction, and microtubule dynamics was revealed by the deregulation of Par3, Claudin1, Scribble, Occludin, ZO-1, phospho-Tau and MAP1B. Also, the Wnt/β-catenin and EphB/EphrinB pathways critical for IEC migration consistently showed greater deregulation at both the time points tested after 56Fe radiation relative to γ -rays. Taken together, our molecular findings correlate with the BrdU pulse labeling data, and demonstrate greater effects of heavy ion 56Fe on IEC migration relative to γ -rays. In summary, our results have demonstrated for the first time that radiation can disrupt cell migration dynamics through alteration of signaling molecules involved in crucial cellular processes and these results have implications for heavy ion space radiation-induced gastrointestinal homeostatic deregulation and carcinogenesis. Citation Format: Santosh Kumar, Shubhankar Suman, Albert Fornace, Kamal Datta. Space radiation-induced persistent DNA damage and alterations in cytoskeletal remodeling pathways affect intestinal epithelial cell migration in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4163.