Gli2-Mediated Shh Signaling Is Required for Thalamocortical Projection Guidance

Abstract

The thalamocortical projections are part of the most important higher level processing connections in the vertebrates and follow a highly ordered pathway from their origin in the thalamus to the cerebral cortex. Their functional complexities are not only due to an extremely elaborate axon guidance process but also due to activity-dependent mechanisms. Gli2 is an intermediary transcription factor in the Sonic hedgehog (Shh) pathway. During neural early development, Shh has an important role in dorsoventral patterning, diencephalic anteroposterior patterning, and many later developmental processes, such as axon guidance and cell migration. Using a Gli2 knockout mouse line, we have studied the role of Shh signaling mediated by Gli2 in the development of the thalamocortical projections during embryonic development. In wild-type brains, we have described the normal trajectory of the thalamocortical axons into the context of the prosomeric model. Then, we have compared it with the altered thalamocortical axons course in Gli2 homozygous embryos. The thalamocortical axons followed different trajectories and were misdirected to other territories probably due to alterations in the Robo/Slit signaling mechanism. In conclusion, the alteration of Gli2-mediated Shh signaling produces an erroneous specification of several territories related with the thalamocortical axons. This is translated into a huge modification in the pathfinding signaling mechanisms needed for the correct wiring of the thalamocortical axons.

Differential Chromatin Architecture and Risk Variants in Deep Layer Excitatory Neurons and Grey Matter Microglia Contribute to Major Depressive Disorder

“…This sSNP is an eQTL and sQTL for a few genes (Fig 5A) including a GTEx eQTL, ZDHHC24, with major regulatory effects on synaptic plasticity 52 and associated through peak-to-gene linkages (r=0.42) with expression of SYT12, a synaptic vesicle protein. Additionally, MDD sSNP in SHANK2 gene (rs11601579; Fig 5C) disrupted binding site accessibility for GLI2 TF, associated with neurodevelopment 53 . This sSNP overlapped ExN1 marker cCRE and significantly correlated with the anti-sense RNA expression of SHANK2 (r=0.6), a postsynaptic density scaffolding protein linked to neuropsychiatric disorders 54,55 .…”

Building thalamic neuronal networks during mouse development

“…They navigate through the thalamic territory using prethalamic axons as scaffolds and following gradients of guidance cues, such as Sema3a and Netrin1 (Quintana-Urzainqui et al, 2020). Thalamocortical axons traverse the entire prethalamus and move through the Slit-free domain of the peduncular hypothalamus until they encounter the diencephalictelencephalic boundary (DTB) (Callejas-Marin et al, 2022). Slit proteins guide thalamocortical axons out of the hypothalamus and they prevent them from crossing the midline (Bagri et al, 2002;López-Bendito et al, 2007;Braisted et al, 2009;Bielle et al, 2011).…”