GO:0022008 neurogenesis: Genes, Functions & Methods

Neurogenesis, defined by the Gene Ontology term GO:0022008, is the biological process responsible for generating cells within the nervous system. This process encompasses the proliferation of neural stem and progenitor cells, their differentiation into neurons and glia, and their functional integration into neural circuits. Neurogenesis is not limited to embryonic development; it continues in discrete adult brain regions, most notably the subgranular zone of the hippocampal dentate gyrus and the subventricular zone. Understanding neurogenesis is fundamental for developmental biology, regenerative medicine, and the study of cognitive disorders. In adult mammals, hippocampal neurogenesis contributes to learning, memory, and mood regulation. Declines in neurogenesis are associated with aging and age-related neurodegenerative diseases, including Alzheimer's disease. Conversely, enhanced neurogenesis or its pharmacological stimulation has been proposed as a therapeutic strategy for depression and cognitive impairment. Research in China has significantly advanced adult neurogenesis studies, particularly regarding environmental enrichment and exercise. At the molecular level, neurogenesis is orchestrated by transcription factors, epigenetic regulators, and signaling pathways. Histone modifications, such as acetylation and methylation, dynamically control the expression of neurogenic genes. Neuroinflammation, mediated by microglia, can suppress or aberrantly activate neurogenesis, linking immune signaling to neural plasticity. This article synthesizes current knowledge on GO:0022008 neurogenesis, its mechanisms, key genes, disease relevance, and experimental models for research.

GO:0022008 neurogenesis is defined as the generation of cells within the nervous system. This includes the production of neurons (neurogenesis sensu stricto) and glial cells from neural stem and progenitor cells, as well as their differentiation, migration, and maturation. The term is a biological process and encompasses both embryonic and adult neurogenesis.

Neurogenesis is essential for brain development, learning, memory, and mood regulation, and its dysfunction is implicated in a wide range of neurological and psychiatric disorders. Adult hippocampal neurogenesis declines with age and is severely impaired in Alzheimer's disease, contributing to cognitive deficits. In depression, chronic stress and neuroinflammation suppress neurogenesis, while antidepressants can enhance it. Understanding the molecular control of neurogenesis offers opportunities for regenerative therapies and disease-modifying treatments.

The following genes and proteins are central to neurogenesis, based on their established roles in neural stem cell maintenance, differentiation, and integration.

Neurogenesis is regulated at multiple levels, including transcriptional, epigenetic, and signaling pathways. Wnt/β-catenin signaling promotes NSC proliferation and neuronal differentiation, while Notch signaling maintains the stem cell pool. Neurotrophins such as BDNF enhance survival and integration of newborn neurons. Neuroinflammation, mediated by microglia and cytokines, can suppress neurogenesis in depression and aging. Histone modifications, including acetylation and methylation, dynamically control the expression of neurogenic genes. Environmental factors such as exercise, enrichment, and stress also modulate neurogenesis rates.

Alzheimer's disease (AD) is characterized by impaired adult hippocampal neurogenesis, which contributes to memory loss and cognitive decline. Amyloid-beta and tau pathology negatively affect NSC proliferation and survival. Neuroinflammation in AD further suppresses neurogenesis. Therapeutic strategies aimed at restoring neurogenesis are under investigation.

Chronic stress and depression are associated with reduced hippocampal neurogenesis, and antidepressants can reverse this deficit. Neuroinflammation and microglial activation play a key role in suppressing neurogenesis in depression. BDNF signaling is a critical mediator linking neurogenesis to mood regulation. Targeting neurogenesis pathways may offer new antidepressant therapies.

Aging leads to a decline in adult neurogenesis, which correlates with cognitive impairment. Reduced NSC proliferation and increased quiescence contribute to this decline. Age-related changes in the neurogenic niche, including inflammation and vascular factors, impair neurogenesis. Understanding these mechanisms may inform interventions to preserve cognitive function.

Disruption of neurogenesis during development can cause neurodevelopmental disorders such as lissencephaly (DCX mutations) and Rett syndrome (MECP2 mutations). Histone modifications and chromatin regulators are frequently mutated in these disorders. Proper epigenetic control is essential for normal neurogenesis. Research into these mechanisms may reveal therapeutic targets.

Immunohistochemistry for markers such as DCX, MKI67, SOX2, and NeuN allows quantification of proliferating progenitors and immature neurons in brain sections. Confocal microscopy and stereology provide accurate cell counts. Live imaging in transgenic reporter mice enables tracking of newborn neurons.

RNA-seq of sorted neural progenitors reveals gene expression changes during differentiation. ChIP-seq for histone modifications (e.g., H3K27ac, H3K4me3) identifies regulatory elements. Single-cell RNA-seq uncovers heterogeneity in neurogenic lineages.

Pooled CRISPR knockout screens in neural stem cells identify genes required for proliferation and differentiation. Arrayed screens with imaging readouts validate candidates. CRISPR activation and interference enable gain- and loss-of-function studies.

Hippocampal-dependent learning and memory tasks (e.g., Morris water maze, novel object recognition) assess functional neurogenesis. Electrophysiology in dentate gyrus slices measures synaptic integration of newborn neurons. These assays link molecular changes to behavior.

Researchers studying neurogenesis-related genes often need to determine whether a candidate gene is causally involved in neural stem cell proliferation, differentiation, or integration. EDITGENE provides comprehensive CRISPR-based services to generate precisely engineered cell and animal models, enabling functional validation of neurogenesis genes.

GO:0022008 neurogenesis is a fundamental biological process that generates neurons and glia throughout life, with critical roles in brain development, memory, and mood. Its dysregulation contributes to Alzheimer's disease, depression, and age-related cognitive decline. Advances in CRISPR-based models and functional genomics are accelerating the discovery of neurogenesis regulators and potential therapeutic targets. Continued research into the molecular and epigenetic control of neurogenesis holds promise for regenerative neurology.