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Tesi etd-03162011-102159


Thesis type
Tesi di dottorato di ricerca
Author
LANCIONI, ALESSIO
URN
etd-03162011-102159
Title
Lack of Mid1, the mouse ortholog of the Opitz syndrome gene, causes abnormal development of the anterior cerebellar vermis
Settore scientifico disciplinare
BIO/09
Corso di studi
NEUROSCIENZE DI BASE E DELLO SVILUPPO
Commissione
tutor Prof. Caleo, Matteo
tutor Meroni, Germana
Parole chiave
  • Cerebellum
  • Development
  • Mid1
Data inizio appello
11/04/2011;
Consultabilità
completa
Riassunto analitico
Opitz G/BBB Syndrome (OS) is a genetic disorder characterized by midline developmental defects. Male patients with the X-linked form of OS, caused by loss-of-function mutations in the MID1 gene, show high variability of the clinical signs. MID1 encodes an ubiquitin ligase that controls Phosphatase 2A but its role in the pathogenesis of the disease is still unclear. Here I report a mouse line carrying a non-functional ortholog of the human MID1 gene, Mid1. Mid1 null mice show the brain anatomical defect observed in patients, i.e. hypoplasia of the anterior portion of the medial cerebellum, the vermis. We found that the presence of this defect correlates with motor coordination, procedural and non-associative learning impairments. The defect is limited to the most anterior lobes of the vermis, the region of the developing cerebellum adjacent to the dorsal midbrain. Analyses at mid-gestation reveal that lack of Mid1 causes the shortening of the posterior dorsal midbrain; the rostralization of the midbrain/cerebellum boundary; and the down-regulation of a key player in the development of this region, Fgf17. Thus, lack of Mid1 causes a mis-specification of the midbrain/cerebellar boundary that results in an abnormal development of the most anterior cerebellar lobes. This animal model provides a tool for further in vivo studies of the physiological and pathological role of the Mid1 gene and a system to investigate the development and function of anterior cerebellar domains.
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