The TCF4 gene encodes Transcription Factor 4, a basic helix-loop-helix (bHLH) transcription factor and a member of the E-protein family. This protein is broadly expressed during nervous system development, demonstrating high expression levels in both embryonic and adult brain tissues, whereas its expression remains relatively low in the majority of normal adult non-neural tissues. As a critical transcriptional regulator, TCF4 modulates downstream gene expression by recognizing and binding to E-box motifs (CANNTG) on DNA. It plays an essential role in neuronal differentiation, synaptogenesis, synaptic plasticity, and the Wnt/β-catenin signaling pathway, and is closely implicated in processes such as cell proliferation, differentiation, and epithelial-mesenchymal transition (EMT) ^[1-2]. Research shows that haploinsufficiency of the TCF4 gene is the primary etiology of Pitt-Hopkins syndrome (PTHS), a disorder primarily characterized clinically by severe intellectual disability, absence of speech, developmental delay, epilepsy, and distinctive facial features ^[3]. Moreover, common variants in the TCF4 gene are significantly correlated with the genetic risk of schizophrenia, autism spectrum disorder (ASD), and other neuropsychiatric conditions ^[4]. Serving as a crucial therapeutic target for transcriptional regulation, TCF4 can be intervened upon via multiple strategies, including small molecule modulators, AAV-mediated gene therapy, antisense oligonucleotides (ASOs), and RNA-based therapies ^[3-5]. Presently, therapeutic approaches targeting TCF4-associated pathways remain largely in preclinical or early-stage development, and are primarily indicated for Pitt-Hopkins syndrome and other neurodevelopmental disorders. With further in-depth research, TCF4 holds promise as a pivotal target for the precision treatment of neurodevelopmental disorders, offering novel directions for mechanistic investigations and therapeutic interventions in related neuropsychiatric diseases. The huTCF4 mouse is a humanized model constructed by gene-editing technology. The region upstream to downstream of mouse Tcf4 was replaced with the region from upstream to downstream of human TCF4. This model can be used for research on Pitt-Hopkins syndrome (PTHS), schizophrenia, autism spectrum disorder (ASD), and other neuropsychiatric disorders, as well as for the development, screening, and preclinical pharmacological and pharmacodynamic evaluation of TCF4-targeted drugs.

Ywhaz is located on chromosome 15 of mice. SgRNA and ssDNA were designed using Nuclease Technology; Ywhaz conditional knockout mice were obtained by high-throughput electroporation of fertilized eggs. After sexual maturity, sperm were collected for cryopreservation.

Slfn14 is located on chromosome 11 of mice. Nuclease Technology will be used to design sgRNA; Slfn14 knockout mice will be obtained by applying high-throughput electroporation of fertilized eggs. After sexual maturity, sperm were collected for cryopreservation.