Analysis of the role of the human-specific gene NBPF14 during human neocortex development and evolution.

• Applicant: Dr. Michael Heide, Ph.D.
• Subject Area: Developmental Neurobiology ; Evolutionary Cell and Developmental Biology (Zoology)
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 525043291

The neocortex is a fascinating brain structure, as it is the seat of human higher cognitive abilities. Different primate species show strong diversity in neocortex morphology in form of size and folding differences culminating in the large and strongly folded human neocortex. The basis for this is established during fetal neocortex development and is primarily controlled by the cortical neural stem and progenitor cells (cNPCs), and is thus controlled by genes that are most likely specifically expressed in these cells. Over the past few years, human-specific genes have received increasing attention as potential major contributors to human neocortex development and evolution. In a previous study we have identified 15 human-specific genes that are specifically expressed in cNPCs. One of these genes, NBPF14, is of special interest, not only as it belongs to the NBPF gene family, which together with its signature protein domain - the Olduvai domain - are correlated with brain size but also as it is co-expressed and co-evolved with another human-specific gene NOTCH2NLB. Both genes are localized in the chromosomal region, which is affected in the 1q21.1 distal syndrome and depending on whether this region is duplicated or deleted, this syndrome is associated with either macrocephaly or microcephaly, respectively. All these points highlight this gene as a promising candidate for a role in human neocortex expansion. The research proposed here will focus on NBPF14 and will analyze its effect(s) on cNPCs. Specifically, we would like to address the following questions. (i) Can NBPF14, when expressed in chimpanzee brain organoids, modify the behavior of chimpanzee cNPCs and does it do this in combination with its co-evolved and co-expressed gene NOTCH2NLB? (ii) Does loss of NBPF14 in human brain organoids affect the behavior of human cNPCs? (iii) Where is NBPF14 localized in the cell and how does it exert there its potential effect(s) on cNPCs? We will address these questions by using genetic modifications of human and chimpanzee brain organoids and by analyzing the effects of these modifications on the behavior of cNPCs. This will allow us to identify a potential role of NBPF14 in the regulation of cNPCs and a potential contribution of this gene in human neocortex development and evolution. Moreover, this would be the first study to analyze a combined effect of two human-specific genes and could, therefore, be a blueprint for future studies of combinations of two or more human-specific genes. Finally, as NBPF14 is localized in the chromosomal region, which is affected in cortical malformations associated with the 1q21.1 distal syndrome, the study of NBPF14 will most likely not only broaden our understanding of cortical development and evolution but also provide novel insights into the formation of cortical malformations.

• DFG Programme: Research Grants