Neurodevelopmental abnormalities in an animal model of Huntington's disease

Abstract

The molecular pathogenesis underlying the selective neuronal subtype vulnerability to late-onset neurodegeneration in Huntington's disease (HD) remains elusive. Clarification of the underlying pathogenic mechanism(s) may therefore require the exploration of others potentially relevant developmental time frames within which the overall disease process may progressively unfold. As cumulative clinical and experimental studies suggest that HD pathogenesis actually commences earlier in life than previously considered applicable, we have hypothesized that mutation in huntingtin causes early alterations that disrupt the course of embryonic neurogenesis and gliogenesis from regional neural stem cells. To examine this hypothesis, we have defined the profiles of specification and progressive maturation of ventral telencephalic lineage species in Hdh-Q18 and Q111 (control and mutant mice respectively) mouse HD knock-in models. Our findings demonstrate that the early elaboration of striatal neuronal species is disrupted in the Hdh-Q111 model of HD. Cell cycle exit of ventral neural progenitors is significantly delayed and the migration and associated lineage maturation of these cell are also deregulated. Moreover, the acquisition of the striatal chemical architecture is developmentally delayed, suggesting progressive maturational abnormalities of medium spiny neuron (MSN) progenitors. Furthermore we demonstrate that gliogenesis is substantially and concurrently affected in Hdh-Q111 embryos, with enhanced glial lineage elaboration coupled with impairments in the progressive maturation of the oligodendrocyte lineage. In addition, we have identified an abnormal increase in the expression of the ventral forebrain-associated gradient morphogen, sonic hedgehog and its downstream target, Gli1 in HD mutant mice. Finally, our in vivo and in vitro experimental studies revealed that cell cycle abnormalities as well as changes in neuronal and glial lineage elaboration are present and may be a consequence of specific patterns of disruption of the developmental Notch signaling pathway. These complex developmental abnormalities define the presence of early molecular and cellular alterations that substantially affect the integrity of the pool of ventral forebrain progenitor cells and the more lineage-restricted MSNs precursors. Such changes have the potential to increase the vulnerability of striatal cells to normally non-pathogenic cell intrinsic as well as environmental stressors of adult life, and may thus contribute to the selective pathology exhibited by HD.