Cajal-Retzius neurons: from migration in the cerebral cortex to the construction of functional and dysfunctional neural circuits – CRsys

The neocortex controls sensory perception, motor behaviors and cognitive functions. These functions rely on a complex architecture of neural networks that begins to be established during embryonic development. This early developmental phase constitutes a major step in the functional emergence of brain circuits. Indeed, studies in the past decades have revealed that abnormal brain development participates to the etiology of several neurological and psychiatric disorders including epilepsy, schizophrenia, autism spectrum disorders or obsessive-compulsive behaviors.

Cajal-Retzius cells (CRs) are among the first-born neurons in the developing cerebral cortex, reside in the superficial layer and die during the first two postnatal weeks. Their best-documented function is to control the radial migration of excitatory neurons. However, over the past years evidence has accumulated for additional roles of CRs in cortical development as in the phenotype of precursor cells, the differentiation of excitatory neurons, the control of inhibitory neuron migration and the development of hippocampal connections. In addition, before their disappearance by the end of the second postnatal week, this transient population is embedded into immature circuits where they mainly receive GABAergic synaptic inputs, suggesting a role in neocortical connectivity.
Notably, persistence of CRs during postnatal life has been detected in pathological conditions, thereby opening the intriguing possibility that the lack of their disappearance may be contributing to dysfunction of cortical circuits.

Recent work, including seminal studies using genetic tracing from Partner 1, revealed that CRs distribution relies on a complex choreography of tangential migration from distinct sources. Their specific repartition in distinct territories of the developing cortex is crucial for the wiring of cortical circuits at multiple levels by controlling cortical patterning and the size of cortical areas dedicated to motor, somatosensory, auditive and visual functions. However, how CR subtypes reach their final position and integrate into immature cortical circuits remain unknown. This proposal aims at testing how life and death of CRs orchestrate the construction of functional cortical circuits. We will study the molecular mechanisms directing the tangential migration and repartition of CR subtypes in the embryonic cortex and how they control the wiring of cortical circuits.

To this end, our consortium of developmental neurobiologists and electrophysiologists with highly synergistic and complementary expertise will study the following specific aims:

Aim 1 - Mechanisms of tangential migration and distribution of Cajal-Retzius neurons. This tasks aims at dissecting the molecular mechanisms mediating CR subtype migration, distribution and full coverage of the neocortex during cortical growth.

Aim 2 - Cajal-Retzius subtype distribution and wiring of cortical circuits. This aims at studying the link between CR subtype position in the marginal zone/layer I, corticogenesis, area formation and the targeting of sensory inputs from the thalamus.

Aim 3 - Persistence of Cajal-Retzius neurons in the postnatal layer I and pathological circuits. This aims at studying how the persistence of CRs might contribute to cortical dysfunction, in particular epilepsy.

This will be achieved through a systemic and multidisciplinary approach coupling molecular and cellular analysis of biological mechanisms using sophisticated mouse genetics (gain and loss-of-function), transcriptome profiling, pharmacological and genetic manipulation of membrane recycling and electrical activity, videomicroscopy, analysis at single cell resolution, cell culture, axonal tracing, electrophysiology, optogenetics and phenotyping using behavioural tests.