Mechanisms of tissue fusion during development.
ABSTRACT Tissue fusion events during embryonic development are crucial for the correct formation and function of many organs and tissues, including the heart, neural tube, eyes, face and body wall. During tissue fusion, two opposing tissue components approach one another and integrate to form a continuous tissue; disruption of this process leads to a variety of human birth defects. Genetic studies, together with recent advances in the ability to culture developing tissues, have greatly enriched our knowledge of the mechanisms involved in tissue fusion. This review aims to bring together what is currently known about tissue fusion in several developing mammalian organs and highlights some of the questions that remain to be addressed.
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ABSTRACT: Failure of facial prominence fusion causes cleft lip and palate (CL/P), a common human birth defect. Currently there are two major hypotheses to explain cleft occurrence. The first holds that the epithelium at these locations is somehow defective for fusion while the second is that the prominences are dysplastic and unable to appose and fuse. Here, using geometric morphometrics, we analyzed facial outgrowth and shape change over time in a novel mouse model exhibiting fully penetrant bilateral CL/P. This robust model is based upon mutations in Tfap2a, the gene encoding transcription factor AP-2α, which has been implicated in both syndromic and non-syndromic human CL/P. Our findings indicate that aberrant morphology and subsequent misalignment of the facial prominences underlies the inability of the mutant prominences to fuse. Exencephaly also occurs in some of the Tfap2a mutants and we observe additional morphometric differences that indicate an influence of neural tube closure defects on facial shape. Molecular analysis of the CL/P model indicates that Fgf signaling is misregulated in the face, and that reducing Fgf8 gene dosage can attenuate the clefting pathology by generating compensatory changes. Further, mutations in either Tfap2a or Fgf8 increase variance in facial shape, but the combination of these mutations restores variance to normal levels. The alterations in variance provide a potential mechanistic link between clefting and the evolution and diversity of facial morphology. Overall, our findings suggest that CL/P can result from small gene expression changes that alter the shape of the facial prominences and uncouple their coordinated morphogenesis, which is necessary for normal fusion.Disease Models and Mechanisms 11/2014; · 5.54 Impact Factor
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ABSTRACT: Unidirectional zippering is a key step in neural tube closure that remains poorly understood. Here, we combine experimental and computational approaches to identify the mechanism for zippering in a basal chordate, Ciona intestinalis. We show that myosin II is activated sequentially from posterior to anterior along the neural/epidermal (Ne/Epi) boundary just ahead of the advancing zipper. This promotes rapid shortening of Ne/Epi junctions, driving the zipper forward and drawing the neural folds together. Cell contact rearrangements (Ne/Epi + Ne/Epi → Ne/Ne + Epi/Epi) just behind the zipper lower tissue resistance to zipper progression by allowing transiently stretched cells to detach and relax toward isodiametric shapes. Computer simulations show that measured differences in junction tension, timing of primary contractions, and delay before cell detachment are sufficient to explain the speed and direction of zipper progression and highlight key advantages of a sequential contraction mechanism for robust efficient zippering. Copyright © 2015 Elsevier Inc. All rights reserved.Developmental cell. 01/2015; 32(2):241-55.
Article: Neural Tube Defects.[Show abstract] [Hide abstract]
ABSTRACT: Neural tube defects (NTDs), including spina bifida and anencephaly, are severe birth defects of the central nervous system that originate during embryonic development when the neural tube fails to close completely. Human NTDs are multifactorial, with contributions from both genetic and environmental factors. The genetic basis is not yet well understood, but several nongenetic risk factors have been identified as have possibilities for prevention by maternal folic acid supplementation. Mechanisms underlying neural tube closure and NTDs may be informed by experimental models, which have revealed numerous genes whose abnormal function causes NTDs and have provided details of critical cellular and morphological events whose regulation is essential for closure. Such models also provide an opportunity to investigate potential risk factors and to develop novel preventive therapies.Annual Review of Neuroscience 07/2014; 37:221-242. · 22.66 Impact Factor