Acta histochemica 109 (2007) 1—14 INVITED REVIEW Palatal fusion – Where do the midline cells go? A review on cleft palate, a major human birth defect Marek Dudas a,c , Wai-Yee Li a , Jieun Kim a , Alex Yang a , Vesa Kaartinen a,b,Ã a Developmental Biology Program, The Saban Research Institute of Childrens Hospital Los Angeles, Mail Stop 35, 4650 Sunset Blvd., Los Angeles, CA 90027, USA b Departments of Pathology and Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA c Institute of Biology and Ecology, P.J. Safarik University in Kosice, Slovakia, EU Received 3 April 2006; received in revised form 26 May 2006; accepted 31 May 2006 KEYWORDS Adhesion; Ankyloglossia and cleft palate; Basal lamina; Cell fate tracking; Craniofacial malfor- mation; Medial edge epithe- lium; Midfacial morpho- genesis Summary Formation of the palate, the organ that separates the oral cavity from the nasal cavity, is a developmental process characteristic to embryos of higher vertebrates. Failure in this process results in palatal cleft. During the final steps of palatogenesis, two palatal shelves outgrowing from the sides of the embryonic oronasal cavity elevate above the tongue, meet in the midline, and rapidly fuse together. Over the decades, multiple mechanisms have been proposed to explain how the superficial mucous membranes disappear from the contact line, thus allowing for normal midline mesenchymal confluence. A substantial body of experimental evidence exists for cell death, cell migration, epithelial-to-mesenchymal transdifferentiation (EMT), replacement through new tissue intercalation, and other mechanisms. However, the most recent use of gene recombination techniques in cell fate tracking disfavors the EMT concept, and suggests that apoptosis is the major fate of the midline cells during physiological palatal fusion. This article summarizes the benefits and drawbacks of histochemical and molecular tools used to determine the fates of cells within the palatal midline. Mechanisms of normal disintegration of the midline epithelial seam are reviewed together with pathologic processes that prevent this disintegration, thus causing cleft palate. & 2006 Elsevier GmbH. All rights reserved. ARTICLE IN PRESS www.elsevier.de/acthis 0065-1281/$ - see front matter & 2006 Elsevier GmbH. All rights reserved. doi:10.1016/j.acthis.2006.05.009 Abbreviations: anoikis, used by some to name the activation of cell death by degradation of the basal lamina; A–P, anterior–posterior; BM, basement membrane (basal lamina, lamina basalis); cataptosis, used by some to name the activation of basal lamina degradation by the cell death within the adjacent epithelium; CL/P, cleft lip and/or palate; CP, cleft palate; GF, GFs, growth factor/factors; ECM, extracellular matrix; EMT, epithelial-to-mesenchymal transdifferentiation or transformation; lacZ, b-galactosidase; ME, medial edge of the palatal shelf; MEE, medial edge epithelium; MED, midline epithelial dysfunction; MES, midline epithelial seam. Ã Corresponding author. Tel.: +1 323 669 2212; fax: +1 323 671 3613. E-mail addresses: marek.dudas@upjs.sk (M. Dudas), vkaartinen@chla.usc.edu (V. Kaartinen).