Chromatin remodeler Arid1a regulates subplate neuron identity and wiring of cortical connectivity

Abstract

Loss-of-function mutations in chromatin remodeler gene ARID1A are a cause of Coffin-Siris syndrome, a developmental disorder characterized by dysgenesis of corpus callosum. Here, we characterize Arid1a function during cortical development and find unexpectedly selective roles for Arid1a in subplate neurons (SPNs). SPNs, strategically positioned at the interface of cortical gray and white matter, orchestrate multiple developmental processes indispensable for neural circuit wiring. We find that pancortical deletion of Arid1a leads to extensive mistargeting of intracortical axons and agenesis of corpus callosum. Sparse Arid1a deletion, however, does not autonomously misroute callosal axons, implicating noncell-autonomous Arid1a functions in axon guidance. Supporting this possibility, the ascending axons of thalamocortical neurons, which are not autonomously affected by cortical Arid1a deletion, are also disrupted in their pathfinding into cortex and innervation of whisker barrels. Coincident with these miswiring phenotypes, which are reminiscent of subplate ablation, we unbiasedly find a selective loss of SPN gene expression following Arid1a deletion. In addition, multiple characteristics of SPNs crucial to their wiring functions, including subplate organization, subplate axon-thalamocortical axon cofasciculation (“handshake”), and extracellular matrix, are severely disrupted. To empirically test Arid1a sufficiency in subplate, we generate a cortical plate deletion of Arid1a that spares SPNs. In this model, subplate Arid1a expression is sufficient for subplate organization, subplate axon-thalamocortical axon cofasciculation, and subplate extracellular matrix. Consistent with these wiring functions, subplate Arid1a sufficiently enables normal callosum formation, thalamocortical axon targeting, and whisker barrel development. Thus, Arid1a is a multifunctional regulator of subplate-dependent guidance mechanisms essential to cortical circuit wiring.

Pf ARID Regulates P. falciparum Malaria Parasite Male Gametogenesis and Female Fertility and Is Critical for Parasite Transmission to the Mosquito Vector

“…For transcription factors to access DNA information, histone proteins must first be repositioned or evicted from the chromosomes, a function that is performed by ATP-dependent chromatin remodeling complexes such as BAF (BRG1/BRM-associated factor) (mammalian SWI/SNF) complexes, which are composed of 14 to 16 individual protein subunits in human cells ( 22 ). These complexes control multiple cellular processes such as cell proliferation, transcriptional activation, differentiation, and chromatin remodeling ( 23 – 25 ). However, chromatin remodeling complexes regulating gametogenesis have not been identified in P. falciparum although, Plasmodium gametocytogenesis and gametogenesis likely requires chromatin remodeling to regulate expression of specific genes.…”

Congenital hydrocephalus: new Mendelian mutations and evidence for oligogenic inheritance

“…Sanger sequencing of the affected fetus confirmed the presence of the frameshift, and its absence in both parents. ARID1A encodes a member of the SWItch/Sucrose Non-Fermenting (SWI/SNF) complex, mediating processes such as the regulation of gene expression, cellular proliferation, apoptosis, differentiation, and the repair of genetic material [ 47 ]. Recently, a conditional Arid1a KO mouse model showed that pancortical Arid1a deletion led to extensive mistargeting of intracortical axons and corpus callosum agenesis [ 47 ].…”

“…ARID1A encodes a member of the SWItch/Sucrose Non-Fermenting (SWI/SNF) complex, mediating processes such as the regulation of gene expression, cellular proliferation, apoptosis, differentiation, and the repair of genetic material [ 47 ]. Recently, a conditional Arid1a KO mouse model showed that pancortical Arid1a deletion led to extensive mistargeting of intracortical axons and corpus callosum agenesis [ 47 ]. Human mutations in this gene are associated with Coffin–Siris syndrome (CSS), a disorder rarely linked to hydrocephalus.…”

Postmitotic accumulation of histone variant H3.3 in new cortical neurons establishes neuronal chromatin, transcriptome, and identity

“…The pathfinding of cortical axons is dependent on correct specification of layer identities ( 41 ), and axon guidance mediated by SP neurons ( 53 , 74 , 75 ). We thus analyzed cortical axon tracts ( Fig.…”