Novel role of bHLH proteins in synaptogenesis: Class I bHLH proteins TCF4 and Daughterless restrict synaptic branching and bouton formation via Neurexin repression in postmitotic neurons

Basic helix‐loop‐helix (bHLH) proteins encompass a highly conserved superfamily of transcription factors that serve as regulators of many developmental processes including neurogenesis. This protein family is divided into six subclasses based on tissue specification, ability to bind DNA at E‐box consensus sequences, and ability to form dimers. Transcription factor 4 (TCF4) is a class I bHLH protein which functions by homo‐ or hetero‐dimerizing with class II/V tissue‐specific bHLH binding partners to control target gene transcription. Haploinsufficiency of TCF4 has been identified as the causative factor in the rare autistic‐like neurodevelopmental disorder, Pitt‐Hopkins Syndrome (PTHS). Similarly, SNPs located in introns of TCF4 have been implemented as a risk factor associated with the psychiatric disorders Schizophrenia and Major Depressive Disorder. Despite the well‐known functions of class I bHLH proteins during development, our laboratory has identified a novel, conserved role for both Tcf4 in mice and its homolog in Drosophila melanogaster , Daughterless ( Da ), with which they are functioning in postmitotic neurons to restrict synaptic branching and bouton formation via restricting transcription of the presynaptic cell adhesion protein, Neurexin. Synaptic branching is one of the ways that neurons remain plastic post development and aberrant branching of the synapses has been associated with defects in neuroplasticity. This suggests that class I bHLH proteins may have a role in neuroplasticity apart from their distinguished role in neurodevelopment. Support or Funding Information NSF Grant: IOS1256114