Mouse Genetics in Development: The Juvenile Hydrocephalus Mouse and Conditional Deletion of Delta-like 1

Mouse genetics in development: the Juvenile hydrocephalus mouse and conditional deletion of Delta-like 1 Oliver Katsumi Appelbe Biological Sciences University of Illinois at Chicago Chicago, Illinois (2012) Dissertation Chairperson: Dr. Peter Okkema The manipulation of mouse genetics to create heritable transgenic mouse models gives researchers a powerful tool in the study of development and disease. This study focuses on two differing transgenic mouse models. Congenital hydrocephalus, despite being a common human developmental disorder, has only one known genetic cause in humans. In this study, the random integration of a transgene led to the disruption of an unstudied gene, Jhy, and the development of juvenile hydrocephalus in homozygous transgenic mice. JHY is relatively well conserved throughout vertebrates, but does not contain any known functional protein domains. The putative Jhy transcript is significantly decreased in hydrocephalic mice, but not completely lost. Jhy transgenic mice develop communicating hydrocephalus with dilation of the brain ventricles being first noticeable at postnatal day 1.5 and becoming fatal around six weeks of age. The ependymal cilia lining the lateral ventricles appear to be disorganized and fewer in number in mutant mice with disorganization of the 9+2 patterning of microtubules apparent. Additional studies on Jhy mice may help in the understanding and treatment of this oft diagnosed human disease. Numerous studies implicate DLK1, a transmembrane protein sharing homology with Notch ligands, in embryonic growth and differentiation. Dlk1 expression is widespread during early development, but is confined to a few specific cell types in adults. Adult Dlk1-expressing tissues include the β-cells of the pancreas and somatotrophs of the pituitary gland. Previously generated Dlk1 null mice (Dlk1Sul-pat), display a partially penetrant neonatal lethality and a complex pattern of developmental and adult phenotypes. Here we describe the generation of a conditional Dlk1 mouse line (Dlk1flox) to facilitate cell type-specific deletion of the Dlk1 gene. Four tissue-specific Cre mouse lines were used to produce individual Dlk1 deletions in key candidates for the Dlk1 phenotype. Contrary to expectations, all of these conditional mice were fully viable, and none recapitulated any aspect of the Dlk1Sul-pat null mice. Dlk1 expression is therefore not essential in β-cells, somatotrophs or endothelial cells, and the tissues responsible for the Dlk1 null phenotype remain to be identified. Dlk1flox mice will continue to provide an important tool for further research into Dlk1.