Human-Specific Genes Can Modify Expressions of Mutations That Lead to Neurodevelopmental Disorders

Recent study findings published in Neuron demonstrate a direct link between human brain evolution and neurodevelopmental disorders. It finds that human-specific genes can modify the phenotypic expression of genetic mutations that lead to an intellectual disability or autism spectrum disorder (ASD) through the regulation of human synaptic neoteny.^1,2

Image credit: Matthieu | stock.adobe.com

The human brain, according to the investigators, stands out among other mammals because of its prolonged development. Synapses, which are critical connections between neurons within the cerebral cortex, can take years to mature in humans, compared with other species, such as mice. The extended development—or neoteny—is believed to be central to humans’ cognitive and learning abilities. For this study, the investigators assessed the function and mechanisms of action of SRGAP2A and SRGAP2B/C in human cortical pyramidal neurons (CPNs) in vivo, using xenotransplantation in the mouse neonatal cortex.^1,2

In human CPNs, to simultaneously downregulate both SRGAP2B/C paralogs—and not SRGAP2A—the investigators utilized a knockdown approach that used 2 independent lentiviral vectors expressing short hairpin RNAs, each targeting different shared regions within SRGAP2B/C transcripts, which are not present in the ancestral SRGAP2A mRNA transcript. For the SRGAP2A gene in human neurons, a short hairpin RNA-mediated knockdown approach directed against SRGAP2A was used. This led to decreased SRGAP2A protein expression in human CPNs while leaving SRGAP2B/C unchanged.²

Further, the investigators identified an evolutionarily conserved and mutually antagonistic interaction between 2 postsynaptic proteins—SRGAP2A and SYNGAP1—that sets the pace of synaptic maturation in mammal CPNs. In addition, the balance is modulated in a species-specific manner by human-specific SRGAP2B/C genes. By downregulating SRGAP2A, the balance is “tipped” toward SYNGAP1, which then sets a neotenic tempo of synaptic maturation in human CPNs.²

Even following 18 months post-transplant, the in vivo xenotransplantation mouse model corresponded to relatively early stages of human CPN development, according to the investigators. Allowing differentiation of human CPNS for longer periods of time may reveal additional roles of SRGAP2B/C in the regulating the final number of synapses in more mature human neurons.²

“We discovered that when you turn off these genes in human neurons, synaptic development speeds up at remarkable levels. By 18 months, the synapses are comparable to what we would expect to see in children between 5 and 10 years old,” said Baptiste Libé-Philippot, postdoctoral fellow, Vanderhaeghen Lab, in a news release. “This mirrors the accelerated synapse development observed in certain forms of ASD.”¹

Further, brain development was previously associated with specific forms of neurodevelopmental diseases, including ASD, and in vitro pluripotent stem cell models have suggested that the altered timing of neuronal differentiation is present in some forms of ASD. The links discovered here between SRGAP2B/C and SYNGAP1 strongly suggest that alterations in the neotenic pace of synaptic maturation in human CPNs may be a significant mechanism present in some forms of NDD. The investigators emphasized that this is important to explore further in clinical research.^1,2

According to the investigators, a limitation of the study is the comparison of tempo of synaptic development of human xenotransplanted CPNs to mouse transplanted CPNs and the inability to extend the comparison to more species, such as primates. Additionally, the investigators noted that the subcellular location of the SRGAP2A and SYNGAP1 proteins used single immunostaining on fixed tissues, which could be assessed in the future using a dual genetic labeling and live in vivo imaging instead. Lastly, the authors said that the detailed molecular mechanisms of function cross-inhibition between SYCAP1 and SRGAP2A are still not fully understood.²

“This work gives us a clearer picture of the molecular mechanisms that shape the slow development of human synapses. It is amazing to find out that the same genes that are involved in the evolution of the human brain also have the potential to modify the expression of specific brain diseases,” said Pierre Vanderhaeghen, MD, PhD,professor, VIB-KU Leuven Center for Brain & Disease Research, in the news release. “This could have important clinical relevance: more research is needed to understand how human-specific mechanisms of brain development affect learning and other behaviors and how their dysregulation can lead to brain disorders. It becomes conceivable that some human-specific gene products could become innovative drug targets.”¹

REFERENCES

1. Vlaams Instituut Voor Biotechnologie. Scientists discover unexpected link between genes involved in human brain evolution and developmental disorders. News release. October 14, 2024. Accessed October 28, 2024. https://www.eurekalert.org/news-releases/1061031

2. Libé-Philippot B, Iwata R, Recupero AJ, et al. Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition. Neuron. 2024. doi:10.1016/j.neuron.2024.08.021