S8 Role for Gli3 in the development of the thalamocortical and corticothalamic tracts in mice

In the adult brain, the thalamocortical tract conveys sensory information from the external environment to the cortex. The cortex analyzes this information and sends back motor information to the thalamus through the corticothalamic tract. During embryogenesis, the ventral telencephalon (VT) plays a major
role in the early development of these tracts. First, two populations of pioneer neurons, located in the lateral and medial ganglionic eminence allow corticothalamic (CTA) and thalamocortical axons (TCA) to enter the VT, respectively. Secondly, the VT forms a permissive corridor which guides TCAs through the MGE. Finally, thalamortical and corticothalamic axons guide
each other once they have met in the VT (‘‘handshake hypothesis’’). The Gli3 transcription factor gene is mutated in several human syndromes which may lead to mental retardation. In particular, acrocallosal syndrome patients are characterized by the absence of the corpus callosum while it is unknown whether
the thalamocortical and corticothalamic tracts form normally in these patients. Here, we present the analysis of thalamocortical tract development in the Gli3 hypomorphic mouse mutant Polydactyly Nagoja (Pdn). We show that in Pdn/Pdn embryos, the telencephalic expression of Gli3 remains graded, but Gli3 mRNA
and protein levels are reduced resulting in an up-regulation of Shh expression and signalling in the ventral telencephalon. These changes mainly affect the development of the lateral ganglionic eminence (LGE). The pallial/subpallial boundary is shifted dorsally and the production of postmitotic neurons is
reduced due to an increased cell cycle length of LGE progenitors. Pdn/Pdn mutants also show abnormal development of several axon guidance cues required for the guidance of corticothalamic and thalamocortical axons through the ventral telencephalon. LGE pioneer neurons which guide corticofugal axons
into the LGE do not form properly, delaying the entry of corticofugal axons into the ventral telencephalon. Moreover, the MGE mantle zone is disorganized. Transplantation experiments demonstrate that the intrinsic ability of the Pdn ventral telencephalon to guide thalamocortical axons is compromised. We
conclude that correct Gli3 levels are particularly important for the LGE’s growth, patterning and development of axon guidance capabilities.