A homeodomain transcription factor controls neural circuits formation in mammalian forebrain.

摘要

Gastrulation brain homeobox 2 gene (Gbx2), encoding a homeodomain transcription factor, is expressed in the mantle zone of the MGE/AEP, the thalamus, the hindbrain and spinal cord in mouse embryos. It has been shown to be a key regulator of genetic programs governing the development of hindbrain. However, its function in the forebrain is poorly understood. In this thesis we demonstrate its role in compartment formation, axon guidance and neural migration of forebrain neurons.;Specifically, we demonstrate here that Gbx2-expressing cells in mouse diencephalon contribute to the entire thalamic nuclear complex. The Gbx2-expressing cells and their descendents form sharp lineage-restriction boundaries. Without Gbx2, cells originating from the thalamus abnormally contribute to the epithalamus and pretectum. Chimeric and genetic mosaic analysis demonstrate that Gbx2 regulates an extracellular signaling pathway that controls segregation of postmitotic thalamic neurons from the neighboring brain structures that do not express Gbx2.;Furthermore, we found that Gbx2-deficient thalamic axons project in abnormal directions. By chimeric analysis, we demonstrate that Gbx2 cell-autonomously specifies the directional outgrowth of TCAs. Through microarray analysis, we found that loss of Gbx2 led to a profound change of in the repertoire of axon guidance molecules. Thalamic neurons in Gbx2 mutant embryos acquired expression profile of axon guidance molecules of epithalamus.;Finally, by performing inducible genetic fate mapping analysis, we demonstrate that cells that express Gbx2 in the medial ganglion eminence contribute exclusively to cholinergic interneurons in the striatum. We show that Gbx2 is essential in restraining neurites growth of immature cholinergic interneurons. Loss of Gbx2 leads to increased complexity of neurites branching and possibly account for the impaired migration of cholinergic progenitor cells. In Gbx2 mutant embryos, early born cholinergic interneuron shift their migration routes, while the late born cells failed to migrate into striatum. As a result, specific deletion of Gbx2 in the ventral telencephalon leads to a significant reduction in the number of cholinergic neurons in the striatum of adult mice. In addition, the absence of later born cells abolishes the graded maturation pattern of striatal cholinergic interneuron population in the caudate-putamen during the first week after birth.