title: Geminin loss causes neural tube defects through disrupted progenitor specification and neuronal differentiation.
abstract: Geminin is a nucleoprotein that can directly bind chromatin regulatory complexes to modulate gene expression during development. Geminin knockout mouse embryos are preimplantation lethal by the 32-cell stage, precluding in vivo study of Geminin's role in neural development. Therefore, here we used a conditional Geminin allele in combination with several Cre-driver lines to define an essential role for Geminin during mammalian neural tube (NT) formation and patterning. Geminin was required in the NT within a critical developmental time window (embryonic day 8.5-10.5), when NT patterning and closure occurs. Geminin excision at these stages resulted in strongly diminished expression of genes that mark and promote dorsal NT identities and decreased differentiation of ventral motor neurons, resulting in completely penetrant NT defects, while excision after embryonic day 10.5 did not result in NT defects. When Geminin was deleted specifically in the spinal NT, both NT defects and axial skeleton defects were observed, but neither defect occurred when Geminin was excised in paraxial mesenchyme, indicating a tissue autonomous requirement for Geminin in developing neuroectoderm. Despite a potential role for Geminin in cell cycle control, we found no evidence of proliferation defects or altered apoptosis. Comparisons of gene expression in the NT of Geminin mutant versus wild-type siblings at embryonic day 10.5 revealed decreased expression of key regulators of neurogenesis, including neurogenic bHLH transcription factors and dorsal interneuron progenitor markers. Together, these data demonstrate a requirement for Geminin for NT patterning and neuronal differentiation during mammalian neurulation in vivo.
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, 320 McDonnell Sciences Building, Campus Box 8103, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Ethan S
authors.initials: ES
authors.lastname: Patterson
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, 320 McDonnell Sciences Building, Campus Box 8103, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Waller
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, 320 McDonnell Sciences Building, Campus Box 8103, 660 S. Euclid Avenue, St. Louis, MO 63110, USA. Electronic address: kkroll@wustl.edu.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Kroll
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D002843:Chromatin; D064248:Geminin / Q000235:genetics*; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D008648:Mesoderm / Q000196:embryology; D051379:Mice; D018345:Mice, Knockout; D054258:Neural Plate / Q000196:embryology*; D054259:Neural Tube / Q000002:abnormalities / Q000196:embryology*; D009436:Neural Tube Defects / Q000235:genetics*; D055495:Neurogenesis / Q000235:genetics*; D054261:Neurulation / Q000235:genetics
chemical_list: D002843:Chromatin; D064248:Geminin; C577997:Gmnn protein, mouse
keywords: Chromatin; Neural tube defect; Neuroepithelium; Neurogenesis