FLRT2 and FLRT3 cooperate in maintaining the tangential migratory streams of cortical interneurons during development

Abstract

Neuron migration is a hallmark of nervous system development that allows gathering of neurons from different origins for assembling of functional neuronal circuits. Cortical inhibitory interneurons arise in the ventral telencephalon and migrate tangentially forming three transient migratory streams in the cortex before reaching the final laminar destination. Although migration defects lead to the disruption of inhibitory circuits and are linked to aspects of psychiatric disorders such as autism and schizophrenia, the molecular mechanisms controlling cortical interneuron development and final layer positioning are incompletely understood. Here, we show that mouse embryos with a double deletion of FLRT2 and FLRT3 genes encoding cell adhesion molecules exhibit an abnormal distribution of interneurons within the streams during development, which in turn, affect the layering of somatostatin1 interneurons postnatally. Mechanistically, FLRT2 and FLRT3 proteins act in a noncell-autonomous manner, possibly through a repulsive mechanism. In support of such a conclusion, double knockouts deficient in the repulsive receptors for FLRTs, Unc5B and Unc5D, also display interneuron defects during development, similar to the FLRT2/FLRT3 mutants. Moreover, FLRT proteins are chemorepellent ligands for developing interneurons in vitro, an effect that is in part dependent on FLRT-Unc5 interaction. Together, we propose that FLRTs act through Unc5 receptors to control cortical interneuron distribution in a mechanism that involves cell repulsion.

Rejection of inappropriate synaptic partners mediated by transcellular FLRT2-UNC5 signaling

“…8A), that blocks UNC5 binding without altering trafficking, surface expression, or interactions with LPHNs (Lu et al, 2015; Seiradake et al, 2014). This so-called FLRT2 UF mutation has been used extensively to test functional consequences of FLRT2-UNC5 signaling (Fleitas et al, 2021; Jackson et al, 2015; Jackson et al, 2016; Lu et al, 2015; Seiradake et al, 2014). Thus, FLRT2 UF provides a useful genetic tool to test whether FLRT2-UNC5 binding is required for DS circuit laminar targeting.…”

“…Thus, there has been substantial interest in understanding both the molecular mechanisms by which these proteins function as well as the specific neurodevelopmental events they control. Previous studies of FLRT-UNC5 receptor-ligand interactions have emphasized effects on UNC5-expressing cells, mediated by UNC5s in their capacity as repulsive guidance receptors (Fleitas et al, 2021; Yamagishi et al, 2011). By contrast, our results reveal that signaling in the reverse direction is also possible: We show that FLRT2-expressing dendrites can be sculpted by UNC5 binding.…”

The genetic regulation of protein expression in cerebrospinal fluid

“…The MR analyses also implicated FLRT2 and RARRES2 in epilepsy. To our knowledge, FLRT2 (fibronectin leucine‐rich transmembrane protein 2) has not been described extensively in relation to epilepsy or seizures, but there is evidence that this cell adhesion molecule is involved in neuronal development, including development of inhibitory cortical circuits (Fleitas et al , 2021 ). RARRES2 (retinoic acid receptor responder protein 2, also known as chemerin) is described as having chemotactic properties during inflammatory responses and serum RARRES2 levels were associated with severity of seizures in children with idiopathic epilepsy (Elhady et al , 2018 ).…”

Cxcr4 and Ackr3 regulate allocation of caudal ganglionic eminence-derived interneurons to superficial cortical layers

“…Using Cxcr4-CreER for permanent genetic labeling, we now show that precursors of PV + and SST + mGE-cINs express Cxcr4 during the early migration period. A third stream of migrating cINs that develops in the subplate depends on FLRT2 and FLRT3 rather than Cxcr4 (Fleitas et al, 2021), probably because Cxcl12 is faintly expressed in this layer (Abe et al, 2015). Since absence of Cxcr4 causes a collapse of the layer specificity of the migration of mGE-cINs (Abe et al, 2014(Abe et al, , 2015Li et al, 2008;Lopez-Bendito et al, 2008) and the signaling of other attractants, such as Neuregulin 3, is dominated by Cxcl12 (Bartolini et al, 2017), Cxcl12 is perceived as the chief guidance factor for mGE-cINs.…”