Ubiquitination is a dynamic and tightly regulated post-translational modification essential for modulating protein stability, trafficking, and function to preserve cellular homeostasis. This process is orchestrated through a hierarchical enzymatic cascade involving three key enzymes: the E1 ubiquitin-activating enzyme, the E2 ubiquitin-conjugating enzyme, and the E3 ubiquitin ligase. The final step of ubiquitination is catalyzed by the E3 ubiquitin ligase, which facilitates the transfer of ubiquitin from the E2 enzyme to the substrate, thereby dictating which proteins undergo ubiquitination. Emerging evidence underscores the critical roles of ubiquitin ligases in neurodevelopment, regulating fundamental processes such as neuronal polarization, axonal outgrowth, synaptogenesis, and synaptic function. Mutations in genes encoding ubiquitin ligases and the consequent dysregulation of these pathways have been increasingly implicated in a spectrum of neurodevelopmental disorders, including autism spectrum disorder, intellectual disability, and attention-deficit/hyperactivity disorder. This review synthesizes current knowledge on the molecular mechanisms underlying neurodevelopment regulated by Cullin-RING ubiquitin ligases—the largest subclass of ubiquitin ligases—and their involvement in the pathophysiology of neurodevelopmental disorders. A deeper understanding of these mechanisms holds significant promise for informing novel therapeutic strategies, ultimately advancing clinical outcomes for individuals affected by neurodevelopmental disorders.

Ubiquitylation is a post-translational modification that modulates protein function and stability. It is orchestrated by the concerted action of three types of enzymes, with substrate specificity governed by ubiquitin ligases (E3s), which may exist as single proteins or as part of multi-protein complexes. Although Cullin (CUL) proteins lack intrinsic enzymatic activity, they participate in the formation of active ubiquitin ligase complexes, known as Cullin-Ring ubiquitin Ligases (CRLs), through their association with ROC1 or ROC2, along with substrate adaptor and receptor proteins. Mammalian genomes encode several CUL proteins (CUL1–9), each contributing to distinct CRLs. Among these CUL proteins, CUL1, CUL3, and CUL4 are believed to be the most ancient and evolutionarily conserved from yeast to mammals, with CUL4 uniquely duplicated in vertebrates. Genetic evidence strongly implicates CUL4-based ubiquitin ligases (CRL4s) in chromatin regulation across various species and suggests that, in vertebrates, CRL4s have also acquired a cytosolic role, which is facilitated by a cytosol-localizing paralog of CUL4. Substrates identified through biochemical studies have elucidated the molecular mechanisms by which CRL4s regulate chromatin and cytosolic processes. The substantial body of knowledge on CUL4 biology amassed over the past two decades provides a unique opportunity to explore the functional evolution of CRL4. In this review, we synthesize the available structural, genetic, and biochemical data on CRL4 from various model organisms and discuss the conserved and novel functions of CRL4s.

Neurodevelopmental disorders (NDDs), including autism spectrum disorder, intellectual disability, and attention deficit hyperactivity disorder, are increasingly recognized as disorders of early brain construction arising from defects in neural stem and progenitor cell (NSPC) proliferation. NSPCs are responsible for generating the diverse neuronal and glial lineages that establish cortical architecture and neural circuitry; thus, their expansion must be tightly coordinated by intrinsic cell cycle regulators and extrinsic niche-derived cues. Disruption of these mechanisms—through genetic mutations, epigenetic dysregulation, or environmental insults—can perturb the balance between NSPC self-renewal and differentiation, resulting in aberrant brain size and connectivity. Recent advances using animal models and human pluripotent stem cell-derived brain organoids have identified key signaling pathways, including Notch, Wnt, SHH, and PI3K–mTOR, as central hubs integrating proliferative cues, while transcriptional and chromatin regulators such as PAX6, CHD8, SETD5, and ANKRD11 govern gene expression essential for proper NSPC cycling. Furthermore, prenatal exposure to teratogens such as Zika virus infection, valproic acid, or metabolic stress in phenylketonuria can recapitulate proliferation defects and microcephaly, underscoring the vulnerability of NSPCs to environmental perturbation. This review summarizes emerging insights into the molecular and cellular mechanisms by which defective NSPC proliferation contributes to NDD pathogenesis, highlighting convergence among genetic and environmental factors on cell cycle control. A deeper understanding of these pathways may uncover shared therapeutic targets to restore neurodevelopmental trajectories and mitigate disease burden.

Phosphodegrons are critical motifs that play a pivotal role in the regulation of protein stability and function via phosphorylation-dependent signaling pathways. These motifs serve as recognition elements for ubiquitin ligases, facilitating the targeted degradation of proteins. By modulating key cellular processes such as cell cycle progression, DNA repair, and apoptosis, phosphodegrons are essential for maintaining cellular homeostasis. Dysregulation of phosphodegrons has been implicated in a wide range of diseases, including cancer and neurodegenerative disorders, highlighting their potential as therapeutic targets. This review provides an overview of phosphodegron functions along with their biological significance in health and disease. Additionally, we discuss current methodologies for studying phosphodegrons and explore emerging trends in their identification and therapeutic targeting. By synthesizing recent advances in the field, this article aims to offer insights into the future directions and challenges in phosphodegron research, ultimately underscoring their importance in cellular regulation and disease pathology.

Ubiquitination is dynamic and tightly regulated post-translational modifications essential for modulating protein stability, trafficking, and function to preserve cellular homeostasis. This process is orchestrated through a hierarchical enzymatic cascade involving three key enzymes: the E1 ubiquitin-activating enzyme, the E2 ubiquitin-conjugating enzyme, and the E3 ubiquitin ligase. The final step of ubiquitination is catalyzed by E3 ubiquitin ligase, which facilitates the transfer of ubiquitin from the E2 enzyme to the substrate, thereby dictating which proteins undergo ubiquitination. Emerging evidence underscores the critical roles of ubiquitin ligases in neurodevelopment, regulating fundamental processes such as neuronal polarization, axonal outgrowth, synaptogenesis, and synaptic function. Mutations in genes encoding ubiquitin ligases and the consequent dysregulation of these pathways have been increasingly implicated in a spectrum of neurodevelopmental disorders, including autism spectrum disorder, intellectual disability, and attention-deficit/hyperactivity disorder. This review synthesizes current knowledge on the molecular mechanisms underlying neurodevelopment regulated by Cullin-RING ubiquitin ligases—the largest subclass of ubiquitin ligases—and their involvement in the pathophysiology of neurodevelopmental disorders. A deeper understanding of these mechanisms holds significant promise for informing novel therapeutic strategies, ultimately advancing clinical outcomes for individuals affected by neurodevelopmental disorders.

Neurodevelopmental disorders (NDDs), including autism spectrum disorder, intellectual disability, and attention deficit hyperactivity disorder, are increasingly recognized as disorders of early brain construction arising from defects in neural stem and progenitor cell (NSPC) proliferation. NSPCs are responsible for generating the diverse neuronal and glial lineages that establish cortical architecture and neural circuitry; thus, their expansion must be tightly coordinated by intrinsic cell cycle regulators and extrinsic niche-derived cues. Disruption of these mechanisms—through genetic mutations, epigenetic dysregulation, or environmental insults—can perturb the balance between NSPC self-renewal and differentiation, resulting in aberrant brain size and connectivity. Recent advances using animal models and human pluripotent stem cell–derived brain organoids have identified key signaling pathways, including Notch, Wnt, SHH, and PI3K–mTOR, as central hubs integrating proliferative cues, while transcriptional and chromatin regulators such as PAX6, CHD8, SETD5, and ANKRD11 govern gene expression essential for proper NSPC cycling. Furthermore, prenatal exposure to teratogens such as Zika virus infection, valproic acid, or metabolic stress in phenylketonuria can recapitulate proliferation defects and microcephaly, underscoring the vulnerability of NSPCs to environmental perturbation. This review summarizes emerging insights into the molecular and cellular mechanisms by which defective NSPC proliferation contributes to NDD pathogenesis, highlighting convergence among genetic and environmental factors on cell cycle control. A deeper understanding of these pathways may uncover shared therapeutic targets to restore neurodevelopmental trajectories and mitigate disease burden.