Novel in vivo models of paediatrics diseases

Mouse models have been used extensively to provide insight into the mechanisms underlying many diseases, to explore the efficacy of possible innovative methods of disease cure as well as testing candidate drugs to predict patient responses. Our laboratory is involved in the production and functional characterization of novel mouse mutant models of human diseases, and in particular, we have developed two models that could be of interest in better understanding pediatric disorders, such as medulloblastoma (MB) and primary ciliary dyskinesia (PCD). MB is one of the most frequently diagnosed pediatric brain tumor and a well established in vivo models of MB are heterozygous for loss-of-function patched 1 (Ptch1) alleles. The mammalian Gpr37l1 gene is extensively expressed in most astrocytic glial cells, including cerebellar Bergmann glia (BG) astrocytes. In BG astrocytes, the murine Gpr37l1 protein has been shown to interact with Ptch1. We observed that the absence of the orphan receptor Gpr37l1 significantly delayed tumor occurrence in Ptch1+/- murine models. We also observed that the absence of Gpr37l1 protein delayed and drastically reduced the occurrence of hyperplastic cerebellar lesions in Ptch1+/- murine models. The newly described Gpr37l1-/-;Ptch1+/- murine line could be suitably applied as an ad hoc model to further investigate the very early phases of Shh-associated MB initiation and progression. Moreover, it could be instrumental to set-up and assess novel genetic or chemical protocols aimed at altering in vivo Gpr37l1's and related protein's functions, for their possible application in novel clinical and pharmacological approaches. Primary ciliary dyskinesia (PCD; OMIM:244400) is a complex disease caused by defects impeding normal function of motile cilia. Mutations in the genes critical for normal development of ciliated cells or protein components of cilia organelles has been associated with PCD. The symptoms of PCD first manifested in childhood, classifying this pathology as a pediatric disease. Because motile cilia are essential for normal functioning of different physiological systems, PCD is a disorder affecting many organs. PCD patients share a common trait: respiratory tract infections, caused by impaired mucociliary clearance, which, in severe cases, can progress to lung destruction. A subset of PCD patients have a defect in left-right body asymmetry, simple or complex cardiovascular malformations, male and female infertility, hydrocephalus, retinitis pigmentosa and renal cysts. We have engineered a mouse model with the knockout of Ccdc151 gene, mutated in human patients, and demonstrated that this mouse line is a true model of human dyskinesia. This finding has been validated by MGI (http://www.informatics.jax.org/allele/genoview/MGI:6360703) by registering this murine model as faithfull PCD model. In this murine line loss of Ccdc151 gene function leads to fast-progressing hydrocephalus and early postnatal lethality. Hydrocephalus phenotype is consistent with the fact that the Ccdc15 gene is expressed in ependymal cells lining of the murine ventricular brain system. The subset of Ccdc151-knockout animals show various laterality defects another trait of the disease. In addition complete azoospermia was observed in a few Ccdc151-null males, which occasionally survived to the point of sexual maturation. Induced loss of Ccdc151 gene function in conditional manner in adult animals causes low sperm counts and defective sperm motility. The Ccdc151 knockout mouse models is a valuable tool to mechanistically studies of human ciliopathies and for testing novel cures. The PCD mouse model will be instrumental to test the novel methodologies to cure hydrpcephalus, a conditions whose treatment has not changes for decades. Further studies of this murine will provide mechanistic insides on development and progression of other features of the PCD disorder as well as possibilities to develop and test novel therapeutic approaches. I suddetti modelli mutanti sono archiviati e disponibili per la distribuzione, con presentazione dei rispettivi dati genotipici e fenotipici, da parte dell'infrastruttura Infrafrontier-European Mouse Mutant Archive (EMMA) presso CNR-Istituto di Biochimica e Biologia Cellulare, sede di Monterotondo Scalo (Roma): ceppo EM:00159 B6.129-Ptch1<tm1Zim>/Cnrm https://www.infrafrontier.eu/search?keyword=00159 ceppo EM:12746 C57BL/6N-Ccdc151<tm1b(EUCOMM)Hmgu>/Cnrm https://www.infrafrontier.eu/search?keyword=12746