Loss of orphan nuclear receptor GCNF function disrupts forebrain development and the establishment of the isthmic organizer

• Published in: Developmental biology 2006-05, Vol.293 (1), p.13-24
• Main Authors: Chung, Arthur C.-K., Xu, Xueping, Niederreither, Karen A., Cooney, Austin J.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Apoptosis - physiology; Cell Differentiation - physiology; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Down-Regulation; Ectoderm - metabolism; Fibroblast Growth Factor 8 - biosynthesis; Fibroblast Growth Factor 8 - genetics; GCNF; Homeodomain Proteins - biosynthesis; Homeodomain Proteins - genetics; Isthmic organizer; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Mesencephalon - abnormalities; Mesencephalon - embryology; Mesencephalon - metabolism; Mice; Mice, Knockout; Midbrain–hindbrain boundary; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Neurons - cytology; Nuclear receptor; Nuclear Receptor Subfamily 6, Group A, Member 1; Organizers, Embryonic - abnormalities; Organizers, Embryonic - embryology; Organizers, Embryonic - metabolism; Otx Transcription Factors - biosynthesis; Otx Transcription Factors - genetics; Phosphoproteins - biosynthesis; Phosphoproteins - genetics; Prosencephalon - abnormalities; Prosencephalon - embryology; Prosencephalon - metabolism; Receptors, Cytoplasmic and Nuclear - deficiency; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - physiology; Somites - metabolism
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2005.12.017

The isthmic organizer, which is located at the midbrain–hindbrain boundary, is important for midbrain development. The mechanism by which the development of the organizer is initiated and maintained is not well understood. Inactivation of the gene encoding the orphan nuclear receptor, GCNF, diminishes the expression of secreted signaling molecules, Fgf8 and Wnt1, the paired box genes Pax2/5, En1/2, and homeodomain transcription factor Gbx2; all of which are essential for isthmic organizer function. In addition, full neuronal differentiation is not observed in the midbrain region of GCNF −/− embryos. Increased cell death may contribute to the loss of midbrain structure in GCNF −/− embryos. These results indicate that GCNF is required for establishment of the isthmic organizer, thereby regulating the midbrain development.