Wieland Huttner

One overarching goal of my research group has been to elucidate the molecular and cellular mechanisms underlying the expansion of the neocortex during human evolution, specifically the increase in the number of cortical neurons generated by cortical stem and progenitor cells during fetal human development. Ultimately, we have aimed at identifying the genomic changes that underlie the increase in neuron number in the human neocortex as compared to other primates.

Towards this goal, we have obtained the following findings.

1. We have characterized the molecular and cellular features of the two classes of neural stem and progenitor cells in the developing neocortex, the apical progenitors (APs) and the basal progenitors (BPs) as well as their various subtypes. Cortical neurons are almost exclusively generated by BPs, and neocortex expansion is thought to be linked to an increased abundance and proliferative capacity of BPs.
2. Comparative analysis of the transcriptomes of the key BP subtype, the basal radial glia (bRG), isolated from embryonic/fetal mouse vs. human neocortex, has led us to identify the human-specific gene ARHGAP11B as a prime candidate to have caused neocortex expansion during human evolution by its ability to amplify BPs (Florio et al. 2015).
3. In support of a central role of ARHGHAP11B in the expansion of the neocortex during human evolution, we have found that physiological expression of ARHGAP11B, i.e. under the control of its own (human) promoter, in fetuses of a New World monkey, the common marmoset (Callithrix jacchus), results in expansion of the primate neocortex and induces cortical folding in this near-lissencephalic primate (Heide et al. 2020). This neocortex expansion was found to be associated with a selective increase in BP, notably bRG, abundance, without an increase in AP abundance, providing direct evidence for the concept that neocortex expansion is linked to an increased abundance and proliferative capacity of BPs (Heide et al. 2020). Moreover, this ARHGAP11B expression was found to result in a specific increase in the level of upper-layer neurons, but not deep-layer neurons, which is a hallmark of evolutionary neocortex expansion (Heide et al. 2020).
4. The ability of the ARHGAP11B protein to amplify BPs was found to be based on a single C-to-G base substitution in the gene, which via altered mRNA splicing results in a novel, human-specific C-terminal protein sequence essential for ARHGAP11B function. The ARHGAP11B protein is imported into, and acts in, mitochondria and amplifies BPs by promoting the metabolic pathway called glutaminolysis, a hallmark of highly proliferative cells.

Taken together, our demonstration that the human-specific gene ARHGAP11B amplifies BPs, increases cortical neuron production and expands the neocortex has provided insight into the genomic changes that underlie the increase in neuron number in the human neocortex as compared to other primates.

A second, and more recent, overarching goal of my research group has been to investigate, in collaboration with Svante Pääbo and his colleagues at the Max Planck Institute for Evolutionary Anthropology (MPI-EVA) in Leipzig, possible differences in the development of the neocortex between modern humans and Neanderthals. To this end, we have focused on proteins that exhibit a small number (typically one) of amino acid substitutions between these two hominins.

Towards this goal, we have obtained the following findings.

1. Following up on our previous observation that metaphase is longer in human than chimpanzee mitotic APs, we have dissected the molecular basis of this phenomenon. We found that three amino acid substitutions in just two human kinetochore proteins, KIF18a (one substitution) and KNL1 (two substitutions, also called CASC5), account for the metaphase prolongation in human APs as compared to APs of the chimpanzee, our nearest living relative (Mora-Bermúdez et al. 2022). We have studied the functional significance of this metaphase prolongation by (i) "humanizing" the corresponding three amino acids in Kif18a and KNL1 in mice, and (ii) anzestralizing the three amino acids in these two proteins in human cerebral organoids. We found that, upon human AP mitosis, this metaphase prolongation is associated with a greater fidelity of chromosome segregation to the AP daughter cells (fewer lagging chromosomes) (Mora-Bermúdez et al. 2022). Interestingly, Neanderthal KIF18a and KNL1 carry the anzestral three amino acids, like the chimpanzee proteins, which implies a shorter metaphase and lesser fidelity of chromosome segregation upon Neanderthal AP mitosis (Mora-Bermúdez et al. 2022). Together, these finding establish that an early step in neocortex development, the mitosis of APs, which impacts the formation of the so-called radial units, differs between modern humans and Neanderthals, with the latter hominins being similar to chimpanzees (Mora-Bermúdez et al. 2022).
2. Another protein with just one amino acid substitution between modern humans (arginine) and Neanderthals (lysine) is transketolase-like-1 (TKTL1). We found that expression of modern human TKTL1, but not Neanderthal TKTL1, in embryonic mouse neocortex selectively increases bRG abundance, and consequently upper-layer neuron production (Pinson et al. 2022). Conversely, "Neanderthalization" of TKTL1 in human cerebral organoids (arginine–>lysine) reduces bRG and neuron abundance (Pinson et al. 2022). The ability of modern human TKTL1 to increase bRG abundance was found to require the pentose phosphate pathway and fatty acid synthesis (Pinson et al. 2022). Interestingly, TKTL1 expression in the fetal human neocortex is highest in the frontal lobe (Pinson et al. 2022). Together, these finding establish that another step in neocortex development, the generation of cortical neurons from bRG, notably in the developing frontal lobe, differs between modern humans and Neanderthals, being greater in modern humans (Pinson et al. 2022).

I plan to continue this second line of research by working together with Svante Pääbo and colleagues at MPI-EVA.

Anneline Pinson, Lei Xing, Takashi Namba, Nereo Kalebic, Jula Peters, Christina Eugster Oegema, Sofia Traikov, Katrin Reppe, Stephan Riesenberg, Tomislav Maricic, Razvan Derihaci, Pauline Wimberger, Svante Pääbo, Wieland B Huttner
Human TKTL1 implies greater neurogenesis in frontal neocortex of modern humans than Neandertals.
Science, 377(6611) Art. No. eabl6422 (2022)
free access article

Felipe Mora-Bermúdez, Philipp Kanis, Dominik Macak, Jula Peters, Ronald Naumann, Lei Xing, Mihail Sarov, Sylke Winkler, Christina Eugster Oegema, Christiane Haffner, Pauline Wimberger, Stephan Riesenberg, Tomislav Maricic, Wieland Huttner, Svante Pääbo
Longer metaphase and fewer chromosome segregation errors in modern human than Neanderthal brain development.
Sci Adv, 8(30) Art. No. eabn7702 (2022)
Full text​​​​​​​

Michael Heide, Christiane Haffner, Ayako Y Murayama, Yoko Kurotaki, Haruka Shinohara, Hideyuki Okano, Erika Sasaki, Wieland Huttner
Human-specific ARHGAP11B increases size and folding of primate neocortex in the fetal marmoset.
Science, 369(6503) 546-550 (2020)
Abstract  |  Reprint   |  Full text

Marta Florio, Mareike Albert, Elena Taverna, Takashi Namba, Holger Brandl, Eric Lewitus, Christiane Haffner, Alex Sykes, Fong Kuan Wong, Jula Peters, E. Guhr, Sylvia Klemroth, Kay Prüfer, Janet Kelso, Ronald Naumann, Ina Nüsslein, Andreas Dahl, Robert Lachmann, Svante Pääbo, Wieland B. Huttner
Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion.
Science, 347(6229) 1465-1470 (2015)
Full text​​​​​​​