Periodic Reporting for period 1 - PRIMAZINC (Deciphering the role of C2H2 zinc finger transcription factors during primate neocortex development and evolution)
Okres sprawozdawczy: 2022-04-01 do 2024-09-30
To achieve this goal, we would like to
(i) identify ZNFs that are differentially active between human, rhesus macaque and common marmoset
(ii) functionally study ZNFs being differentially active in humans vs. non-human primates (rhesus and marmoset) for a role in controlling progenitor activity and behavior
(iii) functionally study ZNFs being differentially active in old-world monkeys (human and rhesus) vs. new-world monkeys (marmoset) for a role in controlling progenitor activity and behavior
While for the initial analysis of gene activity differences between different primate species (objective (i)) in vivo tissue is needed. All the further functional analyses (objectives (ii) and (iii)) will be performed in vitro, mainly by using brain organoids. Brain organoids are 3D multicellular cell aggregates generated from pluripotent stem cells, which model the cytoarchitecture and the cell type composition of certain brain region(s) during a certain developmental time window.
As the experiments for the identification of genes that are differentially active between human, rhesus macaque and common marmoset got delayed, we used a previously generated dataset, which allowed us to identify genes which are present in human but not in non-human primates and present in old-world monkey but not in new-world monkeys, which per definition means that these genes are differentially active between human and non-human primates and between old-world monkeys and new-world monkeys, respectively. This allowed us to study a ZNF, which is only active in human but not in non-human primates. We could show that this gene, when artificially being active in chimpanzee brain organoids, leads to increased cell divisions of progenitor cells while, when deactivated in human brain organoids, leads to reduced cell divisions of progenitors indicating a likely important role of this gene in human neocortex expansion.
Two other ZNF genes are currently in our analysis pipeline. These genes are differentially active between old- and new-world monkeys and could be important players for the pronounced neocortex size and folding differences between these two primate families.
In summary the here described project should result in a better understanding of primate neocortex development and evolution, aiding to understand the origin and the development of our own human neocortex; This could lead to novel insights into the development of cortical malformations, likely allowing future improved genetic counselling and potential strategies for modifying pathophysiological neocortex development. In addition, this will likely provide a better knowledge of the peculiarities of neocortical development of non- human primate models, allowing to assess their suitability as advanced models of human physiological and pathophysiological neocortex development.