Mouse Model of Congenital Hydrocephalus

Congenital hydrocephalus continues to be a difficult disease to treat.  Unfortunately research which explains the exact mechanisms leading to the development of this disease is lacking, likely as a result of no robust models.

In 2011, Stottmann et al, were looking to find and understand the genes involved with neurodevelopment.  In a mouse model, their lab performed a forward genetic screen using ENU to produce novel mutations with the goal of modeling human genetic defects.  During the screen, they produced a mutation which they called “progressive hydrocephalus” (prh).  At birth, these mice appear normal, but at day 14 they are visibly hydrocephalic and do not survive to the weaning period. The image above shows how the mice look compared to wild type (wt) mice.

Recently our lab discovered a gene that is completely devoid in the prh mice called coiled-coil domain containing protein 39 (Ccdc39).  This gene was found to be richly expressed in cells containing cilia and was ultimately found to be required for the assembly of inner dynein arms for the normal ciliary motility in humans and dogs (Merveille et al.).  This is important because according to Lodish et al.:

the inner-arm dyneins are responsible for producing the sliding forces that are converted to bending; this suggests that inner-arm dyneins are essential for bending

Essentially, if the inner dynein of cilia are not assembled correctly, bending forces within the cilia cannot be generated which then would greatly affect motility of the cilia and thus it’s main function.

Our lab has preliminary data that suggests the prh mutation results in loss of ccdc39 protein within the choroid plexus, and this is what may be causing the hydrocephalus phenotype seen in prh mice.  Thus aims of our research include:

  1. Proving the ccdc39 mutation in prh mice is the cause of the hydrocephalus
  2. Then selectively knocking out the ccdc39 gene in the choroid plexus to prove that cilia disruption within the choroid plexus itself is responsible for the hydrocephalus phenotype seen in prh mice
  3. Show that CSF production is abnormal in choroid plexus cells of the ccdc39 mutants

I hope to gather enough data this year to accomplish each of these goals.  I am excited for this year in the lab and am thankful to Dr. Mangano and Dr. Goto for their mentorship.


References
  • Stottmann, R. W., Moran, J. L., Turbe-Doan, A., Driver, E., Kelley, M., & Beier, D. R. (2011). Focusing forward genetics: a tripartite ENU screen for neurodevelopmental mutations in the mouse. Genetics, 188(3), 615–624. http://doi.org/10.1534/genetics.111.126862
  • Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000. Section 19.4, Cilia and Flagella: Structure and Movement. Available from: http://www.ncbi.nlm.nih.gov/books/NBK21698/
  • Merveille, A.-C., Davis, E. E., Becker-Heck, A., Legendre, M., Amirav, I., Bataille, G., et al. (2011). CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nature Genetics, 43(1), 72–78. http://doi.org/10.1038/ng.726