Sall1, Sall2, and Sall4 Are Required for Neural Tube Closure in Mice

Johann Böhm^*, Anja Buck, Wiktor Borozdin^*, Ashraf U. Mannan, Uta Matysiak-Scholze^*, Ibrahim Adham, Walter Schulz-Schaeffer, Thomas Floss^¶, Wolfgang Wurst^¶, Jürgen Kohlhase and Francisco Barrionuevo^*

From the Institut für Humangenetik und Anthropologie,^* Universität Freiburg, Freiburg; the Institut für Humangenetik, Universität Göttingen, Göttingen; the Praxis für Humangenetik, Freiburg; the Abteilung Neuropathologie, Universitätsklinikum Göttingen, Göttingen; and the GSF National Research Center for Environment and Health,^¶ Institute of Developmental Genetics, Neuherberg, Germany

Four homologs to the Drosophila homeotic gene spalt (sal) existin both humans and mice (SALL1 to SALL4/Sall1 to Sall4, respectively).Mutations in both SALL1 and SALL4 result in the autosomal-dominantdevelopmental disorders Townes-Brocks and Okihiro syndrome,respectively. In contrast, no human diseases have been associatedwith SALL2 to date, and Sall2-deficient mice have shown no apparentabnormal phenotype. We generated mice deficient in Sall2 and,contrary to previous reports, 11% of our Sall2-deficient miceshowed background-specific neural tube defects, suggesting thatSall2 has a role in neurogenesis. To investigate whether Sall4may compensate for the absence of Sall2, we generated compoundSall2 knockout/Sall4 genetrap mutant mice. In these mutants,the incidence of neural tube defects was significantly increased.Furthermore, we found a similar phenotype in compound Sall1/4mutant mice, and in vitro studies showed that SALL1, SALL2,and SALL4 all co-localized in the nucleus. We therefore suggesta fundamental and redundant function of the Sall proteins inmurine neurulation, with the heterozygous loss of a particularSALL protein also possibly compensated in humans during development.