Abstract
BackgroundThe cerebellum is responsible for coordinating motor functions and has a unique laminated architecture. Purkinje cells are inhibitory neurons and represent the only output from the cerebellar cortex. Tyrosine hydroxylase (TH) is the key enzyme for the synthesis of catecholamines, including dopamine and noradrenaline, and it is normally not expressed in cerebellar neurons.ResultsWe report here that the low-density lipoprotein receptors (Lrp) 5 and 6, Wnt co-receptors, are required for the development of the cerebellum and for suppressing ectopic TH expression in Purkinje cells. Simultaneous inactivation of Lrp 5 and 6 by Nestin-Cre results in defective lamination and foliation of the cerebellum during postnatal development. Surprisingly, TH is ectopically expressed by Purkinje cells, although they still keep its other neurochemical characteristics. These phenotypes are also observed in the cerebellum of GFAP-Cre;β-cateninflox/flox mice, and AAV2-Cre-mediated gene deletion leads to ectopic TH expression in Purkinje cells of β-cateninflox/flox mice as well.ConclusionsOur results revealed a new role of the canonical Lrp5/6-β-catenin pathway in regulating the morphogenesis of the cerebellum during postnatal development.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0183-1) contains supplementary material, which is available to authorized users.
Highlights
The cerebellum is responsible for coordinating motor functions and has a unique laminated architecture
Low-density lipoprotein receptor 5 (Lrp5) CKO and Low-density lipoprotein receptor 6 (Lrp6) CKO survived into adulthood, but Lrp5/6 dCKO died during the weaning period and exhibited a reduced body weight
We noticed that Lrp5 level was reduced in Lrp6 CKO mice, whereas Lrp6 level was not significantly changed in Lrp5 CKO mice, suggesting that normal expression of Lrp5 might be dependent on Lrp6
Summary
The cerebellum is responsible for coordinating motor functions and has a unique laminated architecture. Purkinje cells are γ-aminobutyric acid (GABA) inhibitory neurons and provide the only output of the cerebellar cortex to deep cerebellar nuclei and other brain regions. Catecholamines include dopamine, noradrenaline and adrenaline, and are critical for regulating many brain functions, including memory, reward, motor control, mood, and rhythm [3]. They are expressed by specific types of neurons, such as dopaminergic neurons in the substantia nigra and noradrenergic neurons in the locus coeruleus, but not in cerebellum [3]. Aromatic L-amino acid decarboxylase (AADC) is responsible for converting L-DOPA to dopamine, whereas β-hydroxylase (DBH) is required for the synthesis of noradrenaline from dopamine [4,5,6]
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