Joyoti Dey, MPH Advisor: Dr. James M. Olson Fred Hutchinson Cancer Research Center & University of Washington Graduate Program Investigating two Oncogenic Mutations in Smoothened with vastly different effects on Cerebellar Development
- Cerebellar Development & Neuronal Circuitry - Role of Shh in Cerebellar Development - Deregulated Shh signaling: SmoA1 & SmoA2 - Medulloblastoma mouse models
Characterization of the SmoA2 mouse model
Represents 10% of total brain, yet > 50% of total neurons
Involved in fine tuning motor movements and balance
One of the first brain structures to begin differentiation, one of the last to attain maturity
The Cerebellum www.nih.nlm.org
Cerebellar Neuronal Circuitry Wang et al. Nature Rev. Neurosci .(2001)
Assessment of Ataxia: “Footprinting” Assay No detectable Ataxia in SmoA2 mice SmoA2 Huntington’s Disease.
Human Cerebellar Dysplasias: Correlation with PNETs Figure: Jeffrey A. Golden & Brian N. Harding. (2004). Developmental Neuropathology Common in apparently normal infant brains Rorke et al (1968) showed histologically, clusters of mature neurons in white matter focal or perivascular GNPs, heterotaxias heterotopias Possible Cause : Inappropriate progenitor cell death and/or neuronal & glial migration Contributory Role in Medulloblastoma: Dysplasias might be targets for neoplastic transformation ( Yachnis et al.(1994), Jay V.(1996)
Bilateral, vertical, orientated folia Enlarged fourth ventricle. Human Cerebellar Dysplasias Right cerebellar hypertrophy & vertical folia Soto-Ares et al. Am J Neuroradiol (2000) Abnormal Arborization of White Matter Heterotopia Normal
SmoA2 & Human CBL Dysplasias: Shared Features Dysplasia & Contiguous Tumor Heterotopia & Heterotaxia Vertical Foliation SmoA2 Wildtype
Wildtype SmoA2 Nov 6, 2008 Abnormal Embryonic Development of SmoA2 Cerebella Ki67 E15.5 dpc
Significant difference in cerebellar development due to SmoA1 and SmoA2 oncogenic mutations
Severe defects in neuronal and glial migration yet no neurobehaviourial abnormalities in the SmoA2 mice
More robust and earlier activation of Shh pathway due to SmoA2 mutation
Several shared key features with Human Cerebellar Dyslasias
Future Directions A connection between Human Cerebellar Dysplasias and the SmoA2 phenotype ? Human SmoA2
Future Directions Determine the molecular basis of abnormal neuronal/glial migration ? ? ?
Future Directions ND2 1kb SmoA1* His6/Myc3 Symptomatic Tumor ND2 1kb SmoA2* HA Investigate Molecular Differences between the SmoA1 and SmoA2 variants P5 P14 P28 P14 P5 P28 Symptomatic Tumor
Acknowledgements Dr. Jim Olson & Our Team !
Acknowledgements FHCRC Experimental Histopathology Core: Dr. Julie Randolph Habecker Dr. Sue Knoblaugh FHCRC Scientific Imaging Core: Dr. Julio Vasquez FHCRC Animal Health Resources Dr. Jon Cooper Tapscott Lab: Laurie Snider Vasioukhin Lab: Dr. Olga Klezovitch