MRC National Institute for Medical Research, London
Science for Health
A common progenitor for striatal interneurons
27 October 2009
Basal ganglia are large clusters of nerve cells in the forebrain that play an important role in the control of movement and cognition. The largest of these clusters, called the striatum, contains different classes of neurons, including the striatal interneurons (SINs). These project locally and, although relatively few in number (2-3% in rodents), they have an important role in co-ordinating the activity of the neural circuits in the basal ganglia. There are many subtypes of SINs but broadly they are subdivided into two non-overlapping groups according to the neurotransmitter they utilize, namely acetylcholine (cholinergic) or gamma-amino butyric acid (GABAergic). So far, the lineage relationship of cholinergic and GABAergic interneurons of the striatum and the molecular mechanisms that control their differentiation are unclear.
Vassilis Pachnis (pictured) and his colleagues in NIMR's Division of Molecular Neurobiology, have now demonstrated that both cholinergic and GABAergic SINs are derived from common precursors generated in the mouse brain during embryogenesis. These precursors express the LIM homeodomain protein Lhx6 (a transcription factor that was identified by the group some years ago) and normally generate GABAergic interneurons. By combining gene expression analysis with studies on mouse mutants, the NIMR researchers have also shown that under the influence of the related transcription factors Lhx7 and Isl1 the Lhx6-expressing progenitors are diverted towards the cholinergic phenotype. These studies indicate that a LIM homeodomain transcriptional code confers cell-fate specification and neurotransmitter identity in neuronal subpopulations of the ventral forebrain.
Striatal interneurons
A Section of the E13.5 forebrain (MGE) comparing expression of Lhx6 (red) and Lhx7 (blue) with a reporter detecting GABAergic neurons (green).
B-D Higher magnifications of boxed regions in A.
E Analysis of adult forebrain tissue (striatum) to compare a marker of the Lhx6 lineage (green) and Lhx7 (blue) with a marker of the cholinergic lineage (red).
Our experiments have identified a set of transcription factors that clearly regulate neuronal cell fate choices by a common progenitor. By working out the mechanisms by which these transcription factors interact to regulate cholinergic versus GABAergic differentiation in the striatum, we hope to understand how two critical neuronal cell types of the mammalian brain are generated during embryogenesis. Obviously, we would like to know to what extent the same factors are used at later developmental stages and even in adult animals to maintain the identity and normal function of cholinergic and GABAergic interneurons in the striatum. Such an understanding is likely to help us design of novel strategies for directing the differentiation of neuronal progenitors towards specific cell types which can be used to restore the activity of diseased striatal neuronal circuits.
Vassilis Pachnis
Original article
Apostolia Fragkouli, Nicole Verhey van Wijk, Rita Lopes, Nicoletta Kessaris and Vassilis Pachnis (2009) LIM homeodomain transcription factor-dependent specification of bipotential MGE progenitors into cholinergic and GABAergic striatal interneurons Development, 136: 3841-51. Publisher abstractSee also
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