Mechanisms controlling the timing of human neuronal maturation: the cellular basis of human brain neoteny.

One important distinctive feature of human brain development is its unusually protracted rate of maturation, or "neoteny" (retention of juvenile features in a mature organism).

Interestingly, neoteny is particularly striking for human cortical neurons, even compared with non-human primates. Despite its crucial importance surprisingly little is known about the mechanisms underlying the timing of brain maturation and neuronal differentiation.

In this frame we made the surprising observation that protracted maturation of human cortical neurons can also be observed even following their transplantation into the mouse developing brain (Espuny-Camacho et al. Neuron 2013; Linaro et al. Neuron 2019), suggesting that intrinsic mechanisms play an important role in the regulation of the timing of neuronal differentiation.

Using gain of function in the mouse and loss/gain of function in human neurons, we now test several classes of candidates, including human-specific genes expressed in maturing neurons and genes that display human-specific patterns of neuronal gene expression. Moreover we combine single RNAseq and crisp/cas9 (CROPSEQ) to perform unbiased functional screens in human neurons for novel genes involved in neuronal development and connectivity, in close collaboration with the Stein lab at CBD (