A Human Accelerated Region regulates forebrain expansion through the regulation of Foxg1 expression during neurulation

FIORE, LUCIANO; MISHARIN, ALEXANDER; JOSHI, NIKITA; MANZANARES, MIGUEL; ACOSTA, SANDRA; ROLLÁN, ISABEL; SIKORA, MARTIN; WILLERSLEV, ESKE; OLIVER, GUILLERMO; IACONO, GIOVANNI; TAKATA, NOZOMU; XU, BEISI; HEYN, HOLGER

Alicante

Congreso; European Developmental Biology Congress; 2019

Spanish Society for developmental biology

How evolution impacted human forebrain development remains an intriguingquestion. Some of the molecular mechanisms implicated in the expansion ofcortical progenitors have been deciphered; however, it is not yet known whether evolutionary events in genomic regions active during early stages of embryonic development, are responsible for the expansion of the human forebrain. Here, we identified an enhancer active at the onset of neurulation located in a human accelerated region (HAR) upstream of Foxg1, a key transcription factor implicated in forebrain development. Foxg1 gain-of-function regulated by the mouse or human enhancer variant results in an increase in neural progenitors.Moreover, humanized forebrain organoids derived from HAR enhancer variantknock-in mouse ESCs are larger and dorsalized, as a consequence of anincreased number of progenitors. These results suggest that human-specificmutations in critical regulatory elements controlling early brain development had a dramatic impact in the expansion and patterning of forebrain progenitors.