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Molecular machinery governing GABAergic neuron specification in the
cerebellum


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Abstract

Although the cerebellum contains a relatively small variety of neurons, the molecular machinery governing neuronal
generation and/or subtype specification is still poorly understood. We identified a novel mutant mouse, cerebelless, which
lacks the entire cerebellar cortex but survives up to the adult stages. Analyses of its phenotypes and identification of its
responsible gene clarified that Ptf1a (pancreas transcription factor 1a), which encodes a bHLH transcription factor, is involved
in cerebellar GABAergic neuron production. Together with recently published papers describing another bHLH gene.

Glutamatergic vs. GABAergic neuron subtypes

Although there are thousands of types of neurons in
the central nervous system, they can largely be
classified into two groups; excitatory and inhibitory
neurons, which are mainly represented by glutamatergic
and GABAergic neurons, respectively. In the
rodent telencephalon, glutamatergic neurons are
produced from the ventricular zone (VZ) of the
dorsal telencephalon and migrate radially, while
GABAergic neurons emerge from the ganglionic
eminence in the ventral telencephalon and migrate
tangentially (Figure 1) (1).

Ptf1a is involved in generating cerebellar
GABAergic neurons


Fluorescence in situ hybridization revealed that the
transgene was inserted in a locus on the second
chromosome, around regions 2A3 2B. The genetic
linkage study localized the transgene between two
markers that were 4.5 Mb apart. Because the process
used for generation of transgenic mice is known to
sometimes cause a deletion of genomic sequences
near the insertion site (25), we searched for possible
genomic deletions, and identified a 313 kb deletion
in the cerebelless genome.

Conclusions

The studies on the cerebelless mutant and its
responsible gene have revealed that a bHLH
transcription factor, PTF1A plays an essential role
in the generation of cerebellar GABAergic neurons.
Furthermore, molecular fate map analyses of Ptf1a
and Math1 have suggested a new model for the
regionalization of cerebellar neuroepithelium. The
strategy for glutamatergic vs. GABAergic neuronal
subtype specification might be similar between the
telencephalon and cerebellum in terms of bHLH
transcription factor involvement in the specification
of the neuroepithelial identities.