FOXP transcription factors in vertebrate brain development, function, and disorders

FOXP transcription factors are an evolutionarily ancient protein subfamily coordinating the development of several organ systems in the vertebrate body. Association of their genes with neurodevelopmental disorders has sparked particular interest in their expression patterns and functions in the brain. Here, FOXP1, FOXP2, and FOXP4 are expressed in distinct cell type-specific spatiotemporal patterns in multiple regions, including the cortex, hippocampus, amygdala, basal ganglia, thalamus, and cerebellum. These varied sites and timepoints of expression have complicated efforts to link FOXP1 and FOXP2 mutations to their respective developmental disorders, the former affecting global neural functions and the latter specifically affecting speech and language. However, the use of animal models, particularly those with brain region- and cell type-specific manipulations, has greatly advanced our understanding of how FOXP expression patterns could underlie disorder-related phenotypes. While many questions remain regarding FOXP expression and function in the brain, studies to date have illuminated the roles of these transcription factors in vertebrate brain development and have greatly informed our understanding of human development and disorders. This article is categorized under: Nervous System Development > Vertebrates: General Principles Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Nervous System Development > Vertebrates: Regional Development.

Keywords: Foxp; autism; brain; gene expression; transcriptional regulation.

Early brain development is a critical epoch for the development of autism spectrum disorder (ASD). In vivo animal models have, until recently, been the principal tool used to study early brain development and the changes occurring in neurodevelopmental disorders such as ASD. In vitro models of brain development represent a significant advance in the field. Here, we review the main methods available to study human brain development in vitro and the applications of these models for studying ASD and other psychiatric disorders. We discuss the main findings from stem cell models to date focusing on cell cycle and proliferation, cell death, cell differentiation and maturation, and neuronal signaling and synaptic stimuli. To be able to generalize the results from these studies, we propose a framework of experimental design and power considerations for using in vitro models to study ASD. These include both technical issues such as reproducibility and power analysis and conceptual issues such as the brain region and cell types being modeled.

Several genes are associated with increased risk for autism spectrum disorder (ASD), neurodevelopmental disorders that present with repetitive movements and restricted interests along with deficits in social interaction/communication. While genetic alterations associated with ASD are present early in life, ASD-like behaviors are difficult to detect in early infancy. This raises the issue of whether reversal of an ASD-associated genetic alteration early in life can prevent the onset of ASD-like behaviors. Genetic alterations of SHANK3, a well-characterized gene encoding a postsynaptic scaffolding protein, are estimated to contribute to ∼0.5% of ASD and remain one of the more replicated and well-characterized genetic defects in ASD. Here, we investigate whether early genetic reversal of a Shank3 mutation can prevent the onset of ASD-like behaviors in a mouse model. Previously, we have demonstrated that mice deficient in Shank3 display a wide range of behavioral abnormalities such as repetitive grooming, social deficits, anxiety, and motor abnormalities. In this study, we replicate many of these behaviors in Shank3 mutant mice. With early genetic restoration of wild-type (WT) Shank3, we rescue behaviors including repetitive grooming and social, locomotor, and rearing deficits. Our findings support the idea that the underlying mechanisms involving ASD behaviors in mice deficient in Shank3 are susceptible to early genetic correction of Shank3 mutations.

Keywords: Phelan–McDermid syndrome; Shank3; autism; autism spectrum disorder; behavior; genetic reversal.

Histone H3 lysine 4 methylation (H3K4me) is extensively regulated by numerous writer and eraser enzymes in mammals. Nine H3K4me enzymes are associated with neurodevelopmental disorders to date, indicating their important roles in the brain. However, interplay among H3K4me enzymes during brain development remains largely unknown. Here, we show functional interactions of a writer-eraser duo, KMT2A and KDM5C, which are responsible for Wiedemann-Steiner Syndrome (WDSTS), and mental retardation X-linked syndromic Claes-Jensen type (MRXSCJ), respectively. Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression. Double mutation of Kmt2a and Kdm5c clearly reversed dendritic morphology, key behavioral traits including aggression, and partially corrected altered transcriptomes and H3K4me landscapes. Thus, our study uncovers common yet mutually suppressive aspects of the WDSTS and MRXSCJ models and provides a proof of principle for balancing a single writer-eraser pair to ameliorate their associated disorders.

Chromatin regulates spatiotemporal gene expression during neurodevelopment, but it also mediates DNA damage repair essential to proliferating neural progenitor cells (NPCs). Here, we uncover molecularly dissociable roles for nucleosome remodeler Ino80 in chromatin-mediated transcriptional regulation and genome maintenance in corticogenesis. We find that conditional Ino80 deletion from cortical NPCs impairs DNA double-strand break (DSB) repair, triggering p53-dependent apoptosis and microcephaly. Using an in vivo DSB repair pathway assay, we find that Ino80 is selectively required for homologous recombination (HR) DNA repair, which is mechanistically distinct from Ino80 function in YY1-associated transcription. Unexpectedly, sensitivity to loss of Ino80-mediated HR is dependent on NPC division mode: Ino80 deletion leads to unrepaired DNA breaks and apoptosis in symmetric NPC-NPC divisions, but not in asymmetric neurogenic divisions. This division mode dependence is phenocopied following conditional deletion of HR gene Brca2. Thus, distinct modes of NPC division have divergent requirements for Ino80-dependent HR DNA repair.

2021Boston Children’s HospitalDaniel Nunez HuarachaCharles Nelson

2021Johns Hopkins UniversityHeather Volk

2021Alycia Halladay