Separate research groups have reported new insights into the process of neurogenesis during development and adulthood, respectively. Their papers appeared in the July 6, 2021, online issue of Cell Reports.
The brain is easily the most complex organ in the body, and developmental neurogenesis is a correspondingly complex process. And good model systems for the development of the brain are challenging to find. The human forebrain is uniquely complex, but also differs from animal brains in ways that can be very basic. TDP-43, for example, which plays a role in amyotrophic lateral sclerosis (ALS), has different binding partners in humans than in animals.
In recent years, 3D cell cultures that allow different cell types to organize into so-called organoids have allowed researchers to probe brain development in ways that were inaccessible. Methods exist that allow brain organoids to survive and develop for nearly 2 years, modeling the developmental processes of late pregnancy and early postnatal life.
And while many brain disorders are the result of complex gene-environment interactions that cannot be modeled adequately in cell culture, organoids are also useful to probe the molecular underpinnings of those disorders that are the result of relatively simple genetic events.
Among such events are microdeletions, the loss of less than 5 million base pairs from a chromosome. "Micro," of course, is a relative term. Microdeletions are not evident under a microscope, but 5 million base pairs can easily span several genes. When they do, ascribing specific causality for specific symptoms within the microdeletion is difficult to do.
Researchers from Washington University in St. Louis used organoids to dissect the causal factors for a syndrome caused by a microdeletion in 17q11.2. This region includes the gene for neurofibromin. Mutations in neurofibromin cause type 1 neurofibromatosis (NF1), a developmental disorder that affects multiple organs including the brain.
The 17q11.2 deletion, which typically spans 1.4 million base pairs, causes a severe type of NF1 whose symptoms include developmental delays and intellectual disability. The microdeletion leads to a total loss of the neurofibromin gene. But it also spans more than a dozen other protein-coding genes, as well as four microRNAs, prompting the authors to investigate whether other genes than neurofibromin played a role in the neurodevelopmental symptoms.
The team first developed organoids from iPSCs of patients with microdeletion 17q11.2, and demonstrated that the abnormalities in those organoids could not be recapitulated through lack of only neurofibromin. They next used several different approaches to identify reduced expression of the cytokine receptor-like factor 3 (CRLF3) gene as responsible for the severe neurodevelopmental effects.
The authors also reported "a higher autistic trait burden in NF1 patients harboring a deleterious germline mutation in the CRLF3 gene" in their paper. They concluded that "while CRLF3 has not been previously implicated as an autism risk gene, it constitutes a potential therapeutic target and a risk assessment tool in future studies involving larger numbers of individuals, with a focus on its sensitivity and specificity for predicting ASD [autism spectrum disorder] symptomatology in children with NF1."
Another paper in the same issue of Cell Reports reported on the link between neurogenesis and neuronal activity in the adult brain.
Compared to most other cell types, neuronal division during adulthood is an extremely rare event. But those rare new neurons play important roles in brain plasticity. Brain plasticity underlies the brain's ability to learn, and at the level of neuronal connections, plasticity is activity dependent. Connected neurons that fire at the same time will strengthen their connections, while a failure to be active at the same time weakens neuronal links.
Researchers at Nanyang Technological University wanted to see whether neuronal activity also plays a role in where new neurons are born in the adult brain. They showed that in freely moving adult rats, neurons were more likely to be born in regions that were active, and less likely to appear in regions where there was inhibitory interneuron activity.
The authors suggested that "local excitatory circuits may recruit new neurons selectively nearby and at the same time induce the activation of surrounding inhibitory interneurons, which in turn limits the spatial range of the local recruitment of new neurons." Such interplay between different types of neuronal activity could be "a mechanism by which new neurons are selectively recruited into the microcircuit activated during a recent experience... [and] the key to understanding the contribution of adult neurogenesis to adaptive brain functions at the microcircuit level." (Uemura, M. et al. Cell Rep 2021, 36(1): 109324; Wegscheid, M.L. et al. Cell Rep 2021, 36: 109315).