Evolutionary conserved canonical BMP activity controls cortical neurogenesis

Bone morphogenetic proteins (BMPs) are multitasking secreted factors from the Transforming Growth Factor-β (TGF-β) superfamily, members of which play crucial roles during amniote development. BMPs and their canonical signalling through the SMAD1/5/8 transcription factors are known to play key roles during the early steps of central nervous system (CNS) development, influencing events such as neural induction, neural tube closure and dorsal-ventral patterning. However, their contribution to the later stages of amniote CNS formation is much less clear. Here we reveal that SMAD1/5 fulfill an evolutionarily conserved role during cortical neurogenesis. Gain- and loss-of-function experiments in chick embryos show that SMAD1/5 activity supports the self-amplification of cortical radial glial cells (RGCs) and impedes their premature differentiation and exhaustion. Using conditional Smad1/5wt/fl;Nestin:Cre+/0 (SmadNes) mutant mice, we reveal this role to be evolutionarily conserved in mammals. The sustained reduction in SMAD1/5 activity in mouse RGCs increases the generation of early-born cortical excitatory neurons at the expense of late-born neurons. These SmadNes mutant mice also present microcephaly and overall growth retardation. Genome-wide analysis of the transcriptional changes caused by SMAD1/5 inhibition in cortical RGCs indicates that SMAD1/5 positively regulate the activity of YAP, a master regulator of cell growth and organ size. These findings identify an evolutionarily conserved role for canonical BMP signalling in stem cell maintenance and tissue growth during cortical neurogenesis. We anticipate that the regulation of YAP activity by canonical BMP signalling extends beyond the context of cortical neurogenesis and might be a crucial event regulating growth throughout the CNS and in other tissues.