TheGli3Hypomorphic MutationPdnCauses Selective Impairment in the Growth, Patterning, and Axon Guidance Capability of the Lateral Ganglionic Eminence

Abstract

Previous studies have defined a requirement for Sonic hedgehog (Shh) signaling in patterning the ventral telencephalon, a major source of the neuronal diversity found in the mature telencephalon. The zinc finger transcription factor Gli3 is a critical component of the Shh signaling pathway and its loss causes major defects in telencephalic development. Gli3 is expressed in a graded manner along the dorsoventral axis of the telencephalon but it is unknown whether Gli3 expression levels are important for dorsoventral telencephalic patterning. To address this, we used the Gli3 hypomorphic mouse mutant Polydactyly Nagoya (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 upregulation of Shh expression and signaling. These changes mainly affect the development of the lateral ganglionic eminence (LGE), with some disorganization of the medial ganglionic eminence mantle zone. The pallial/subpallial boundary is shifted dorsally and the production of postmitotic neurons is reduced. Moreover, LGE pioneer neurons that guide corticofugal axons into the LGE do not form properly, delaying the entry of corticofugal axons into the ventral telencephalon. Pdn/Pdn mutants also show severe pathfinding defects of thalamocortical axons in the ventral telencephalon. 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.

Activin A directs striatal projection neuron differentiation of human pluripotent stem cells

“…However, the above-mentioned ESC studies do not necessarily suggest a direct role for Shh in LGE/striatal fate specification. Furthermore, genetic study of Gli3 hypomorphic mutant mice, which exhibit elevated Shh signalling in the ventral forebrain, revealed aberrant patterning of the LGE exemplified by ectopic expression of MGE characteristics (Magnani et al, 2010); this study suggests that the primary target of Gli3 suppression is the MGE.…”

Gli3 Controls Corpus Callosum Formation by Positioning Midline Guideposts During Telencephalic Patterning

“…CC in Pdn mutants could either be caused by the disorganization of midline guideposts or by a primary failure of callosal axons to navigate in the midline region leading to the formation of Probst bundles and to a secondary redistribution of guideposts. Previous marker and BrdU birthdating analyses in Pdn/Pdn mutants failed to find major defects in cortical lamination (Magnani et al 2010). Moreover, Satb2 upper layer callosal projection neurons are borne at E15.5 ( Supplementary Fig.…”

“…Organotypic slice cultures of rostral levels of the embryonic mouse telencephalon were prepared as previously described (Magnani et al 2010). Brain slices were cultured on polycarbonate culture membranes (8-μm pore size; Corning Costar) in organ tissue dishes containing 1 mL of medium supplemented with glutamine, glucose, penicillin, and streptomycin).…”

“…2C). In contrast, corticofugal axons project into the lateral cortex and striatum under these conditions (Magnani et al 2010). These results show that normal levels of Gli3 are not required to generate callosal neurons with the ability to project their axons across the midline, but indicate a requirement for Gli3 in the generation of the midline guideposts.…”

“…Moreover, Gli3 functions in axon pathfinding in the forebrain. The Gli3 hypomorphic mouse mutant Polydactyly Nagoya (Pdn) shows defects in the corticothalamic and thalamocortical tracts (Magnani et al 2010) and lacks the CC (Naruse et al 1990) though for unknown reasons. Using transplantation experiments, we here demonstrate that midline abnormalities are primarily responsible for agenesis of the corpus callosum (ACC).…”