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Abstract :
[en] Balance between the proportion of excitatory projection neurons (PNs) and inhibitory interneurons (cINs), is critical for the proper function of the adult cortex. During development, PNs are generated in the ventricular zone on the dorsal forebrain, and the cINs are born distantly in the ganglionic eminences (GEs) in the ventral forebrain. The cINs migrate long distances towards the cortex, where they mature and form neuronal circuits with PNs. When migrating, cINs are guided by intrinsic mechanisms and numerous diffusible cues including the chemokine Cxcl12 secreted by intermediate progenitors (IPs), which act mostly as precursors of superficial PNs. Previous work in our laboratory demonstrated that cINs also communicate with IPs during their migration via diffusible cues, but their identity remains to be elucidated. Using a mice model where carboxypeptidase 1 (CCP1) is deleted from cINs, an advanced cohort of cINs populates the cortical plate, leading to an increased proliferation of IPs as well as the subsequent generation of supernumerary superficial PNs. Here we will use human cerebral assembloids to model the impact of cIN migration in vitro, where dorsally patterned cortical organoids are fused with ventrally patterned organoids, and they recapitulate the tangential migration of cINs towards the dorsal region. Using patient derived IPS with loss of function of CCP1, we modelled an advancement front of migration compared with control cell lines. We then analysed if the proliferation of cortical progenitors is altered upon an increased interneurons migration, showing that specifically IPs residing in the assembloids rosettes presented an increased proliferation rate. These results suggest that the cIN-IP crosstalk is conserved during human cortex development. We will further investigate the molecular identity of this crosstalk via proteomic assay.
