This study shows that CELF2, an RNA-binding protein, is essential for healthy brain development. Researchers found that loss of CELF2 disrupted the organization and maturation of neurons, altered the activity of hundreds of genes, and reduced levels of CAMK2A, a key protein involved in synaptic function. The findings highlight how defects in RNA regulation can affect brain development and may contribute to neurodevelopmental disorders.
Dr. Chen is the holder of the Bartell Zachry Memorial Distinguished Professorship for Research in Neurodegenerative Diseases, an Associate Professor with the Department of Cell Systems and Anatomy, and an investigator with the Sam and Ann Barshop Institute for Longevity and Aging Studies.
CELF2-dependent RNA Regulation Supports Cortical Architecture and Synaptic Stability During Early Brain Development
Ishana Syed, Jing Jiang, Su-Hyuk Ko, Shaoting Chen, Zhao Zhang, Zhijie Liu, Lizhen Chen
Mol Neurobiol. 2026 May 26;63(1):653. doi: 10.1007/s12035-026-05933-6.
Abstract
RNA regulation plays a central role in neurodevelopment by coordinating neuronal differentiation, migration, and circuit formation. The CUGBP Elav-like family member 2 (CELF2) is an RNA-binding protein with established roles in alternative splicing and mRNA regulation, yet its function in the developing brain remains poorly defined. Here, we investigated the role of CELF2 during neurodevelopment using a constitutive Celf2 knockout (KO) mouse model. Celf2 knockout pups exhibited neonatal lethality accompanied by impaired neuronal maturation and disrupted cortical organization. Bulk RNA sequencing revealed widespread transcriptional dysregulation, while splicing analyses identified reduced exon inclusion in multiple neurodevelopmental transcripts following CELF2 loss. Notably, Camk2a transcript and protein levels were markedly reduced in knockout brains, consistent with CELF2 binding to the Camk2a 3’UTR. Functional studies in C. elegans demonstrated that expression of human CAMK2A partially rescued synaptic puncta deficits in unc-75 (CELF ortholog) mutants, supporting a conserved role for CELF-family proteins in synaptic maturation. Histological analyses revealed reductions in Nestin- and Doublecortin-positive immature neurons, thinning of upper cortical layers, and decreased CAMK2A expression. Single-nucleus RNA sequencing further revealed selective reductions in upper layer II/III excitatory neuron populations in the cortex. Cellular trajectory and pseudotime analyses revealed delayed maturation in certain cell types but accelerated progression in others in Celf2 KO animals. Together, these findings establish CELF2 as a critical post-transcriptional regulator required for neuronal maturation and architectural stability during early brain development and highlight how disruption of RNA regulatory programs may contribute to neurodevelopmental disorders.
Keywords: Cortical organization; Neurodevelopment; Neuronal maturation; RNA-binding proteins; Single nucleus RNA sequencing; Synaptic development.