Calcium dynamics tune developmental tempo to generate evolutionarily divergent axon tract lengths

Abstract

The considerably slow pace of human brain development correlates with an evolutionary increase in brain size, cell numbers, and expansion of neuronal structures, with axon tracts undergoing an even greater evolutionary increase than other neuronal domains. However, whether tempo is responsible for these differences in magnitude, and how, remains to be determined. Here, we used brain organoids to investigate this and observed that human axon tracts spend more time growing and extend farther compared to those of mice, independent of their tissue environment. Single cell RNA sequencing analysis pointed to a subset of calcium-permeable ion channels expressed throughout neuron development, including during axon tract outgrowth. Calcium imaging during early neuron development consistently revealed a reduced calcium influx in human neurons compared to mouse neurons. Stimulating calcium influx and increasing cAMP levels resulted in premature halting of axon tract outgrowth and shorter axon tracts, mimicking the mouse phenotype, while abrogating calcium influx led to an even longer phase of axon tract outgrowth and longer axon tracts in humans. Thus, evolutionary differences in calcium regulation set the tempo of neuronal development, by extending the time window to foster the more elaborated human neuron morphology.

Competing Interest Statement

MAL is an inventor on patents covering cerebral organoids, and is co-founder and advisory board member of a:head bio.

Footnotes

* Authorship adjusted with addition of two authors.