Otx2 regulates the extent, identity and fate of neuronal progenitor domains in the ventral midbrain
2004
The specification of distinct neuronal cell-types is controlled by inducing
signals whose interpretation in distinct areas along the central nervous
system provides neuronal progenitors with a precise and typical expression
code of transcription factors. To gain insights into this process, we investigated the role of Otx2 in the
specification of identity and fate of neuronal progenitors in the ventral
midbrain. To achieve this, Otx2 was inactivated by Cre recombinase
under the transcriptional control of En1 . Lack of Otx2 in the
ventrolateral and posterior midbrain results in a dorsal expansion of Shh
expression and in a dorsal and anterior rotation of the midbrain-hindbrain
boundary and Fgf8 expression. Indeed, in this mutant correct
positioning of the ventral site of midbrain-hindbrain boundary and
Fgf8 expression are efficiently controlled by Otx1 function, thus
allowing the study of the identity and fate of neuronal progenitors of the
ventral midbrain in the absence of Otx2. Our results suggest that Otx2 acts in
two ways: by repressing Nkx2.2 in the ventral midbrain and maintaining the
Nkx6.1-expressing domain through dorsal antagonism on Shh. Failure of this
control affects the identity code and fate of midbrain progenitors, which
exhibit features in common with neuronal precursors of the rostral hindbrain
even though the midbrain retains its regional identity and these neuronal
precursors are rostral to Fgf8 expression. Dopaminergic neurons are
greatly reduced in number, red nucleus precursors disappear from the ventral
midbrain where a relevant number of serotonergic neurons are generated. These
results indicate that Otx2 is an essential regulator of the identity, extent
and fate of neuronal progenitor domains in the ventral midbrain and provide
novel insights into the mechanisms by which neuronal diversity is generated in
the central nervous system.
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