Retinoic acid controls early neurogenesis in the developing mouse cerebral cortex

Abstract

A tight regulation of neuron production is required to generate a functional cerebral cortex and is achieved by a proper balance between proliferation and differentiation of progenitor cells. Though the vitamin A (retinol) active derivative retinoic acid (RA) has been implicated as one of the signals acting during mammalian forebrain neurogenesis, its function at the onset of neurogenesis as well as during establishment of cortical layers and neuronal subtypes remains elusive. One limitation is that murine mutants for genes encoding key enzymes involved in RA synthesis die during early embryonic development. We analysed corticogenesis in Rdh10 null mutants, in which an RA deficiency is generated as the intracellular retinol to retinaldehyde conversion is abolished. When analysed at the latest stage before lethality occurs (embryonic day [E]13.5), the mutants show smaller telencephalic vesicles and the thickness of their cortical plate is strongly reduced. The first progenitors formed in the cortical plate are radial glial (RG) cells which generate neurons either directly, or through an indirect mechanism involving the production of intermediate neuronal progenitors (INPs) which then give rise to neurons. We show that in absence of RA, the RG progenitors proliferate less and prematurely produce neurons, leading to their depletion at E11.5. Furthermore, we could demonstrate that lack of RA impairs the generation of INPs at E13.5 and affects the cell cycle exit of progenitor cells during corticogenesis, altogether leading to a deficit in projection neurons and to microcephaly.