A Theoretical and Experimental Examination of Cell Lineage Relationships among Cerebellar Purkinje Cells in the Mouse

Abstract

In this paper, we continue our examination of the role of cell lineage in the development of the cerebellar Purkinje cell population of the mouse. The analysis of Purkinje cell lineage is based on counts of the number of wild-type Purkinje cells in +/ Lc ↔ wild-type chimeras. +/ Lc Purkinje cells undergo a cell autonomous degeneration early in post-natal development leaving variable numbers of wild-type Purkinje cells in chimeric animals. Using theoretical, statistical, and experimental approaches, we have tested various developmental models to account for the numerical development of Purkinje cell numbers in the +/ Lc ↔ wild-type chimeras. We have analyzed models based on the assumption that cell lineages are irrelevant to Purkinje cell development, as well as our own previous hypothesis that Purkinje cells descend from a small number of progenitor cells selected during the early stages of neurogenesis. The theoretical approach calculates the distributions of Purkinje cell numbers in hypothetical +/ Lc ↔ wild-type chimeras and inbred mice based on both clonal and nonclonal hypotheses of neuronal development. Variations of the model are compared with published cell counts from +/ Lc ↔ C3H/HeJ, +/ Lc ↔ C57BL/6J, +/ Lc ↔ AKR/J chimeras, and C3H/HeJ inbred mice. The statistical approach assesses the significance of the fits of the observed data with different variations of the model by Monte Carlo simulation techniques. The results of the comparison suggest that our observed data is more likely to be explained by a clonal model of development than by alternate models in which cell lineages play a minor role. Our experimental approach describes a new +/ Lc ↔ C3H/HeJ chimera in which all of the Purkinje cells (>7900) are found on one side of the brain. We have analyzed this chimera with respect to clonal and nonclonal models of Purkinje cell development. The extreme asymmetric distribution of Purkinje cells provides added support to the hypothesis that there is a small number of progenitor cells that generate Purkinje cells. Our findings lead to the conclusion that while not all alternate models of mammalian CNS development can be completely excluded, the early progenitor hypothesis is the most probable model of Purkinje cell development.