Weaver is a pleiotropic mutation consisting of a single base-pair substitution in a gene coding for a G-protein-activated inward-rectifying potassium channel, Girk 2. The present work revises the manner in which the expression of the weaver gene affects the generation and survival of several neuronal populations (midbrain dopaminergic neurons, Purkinje cells and deep nuclei neurons in the cerebellum). Using [3H]TdR autoradiography -to determine developmental timetables- and tyrosine hydroxylase immunocytochemistry -to identify dopamine neurons- we shown that depending on neuronal type, degree of vulnerability to the lethal action of the mutant gene is related to temporal and spatial patterns of neuron formation. In homozygous weaver mice (wv/wv) collected at embryonic day 19 or postnatal day (P) 8, no loss of dopamine (DA) neurons was observed in the midbrain. In the same period, a substantial depletion of Purkinje cells (PCs) and deep cerebellar nuclei (DCN) neurons was observed. When labeling profiles were measured at P8, the inferred time of origin was similar between +/+ and wv/wv for each neuronal population considered. These observations suggest that the proliferative behavior of DA neuron precursor, as well as subsequent steps in neuronal development, seem to be unaffected by the expression of the mutant gene. On the other hand, results in the cerebellum provided two main clues: (I) loss of PCs and DCN neurons occurs very early in the development of the weaver homozygotes, and (II) the weaver gene is targeting these macroneurons irrespective of their time of their birth. When mutant mice survive until P20 or P90, several findings can be deduced: the weaver gene kills postmitotic late-generated DA cells, depending on parameters such as animal age, the midbrain area studied and spatial arrangements. Loss of tyrosine hydroxylase reactive cells is linked to timetables; susceptibility to the weaver gene expression is therefore built into the midbrain dopaminergic neural system during development. Moreover, we observed that the neurogenetic gradients of DA neurons were disturbed in the weaver homozygotes. When the weaver cerebellum was examined at P90, autoradiographic studies indicated that the deficit of PCs and DCN neurons was again random across age, and no spatial differences in the PCs settled pattern were observed. In spite of this, depletion of these macroneurons was regionally variable, related to lateral-to-medial gradients of vulnerability as well as to fissures or foliar crowns, depending on the vermal lobe or the hemispheric lobule examined.
|Original language||English (US)|
|Title of host publication||Brain Research Developments|
|Publisher||Nova Science Publishers, Inc.|
|Number of pages||36|
|State||Published - Jan 1 2011|
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