Transcriptional and epigenetic characterization of early striosomes identifies Foxf2 and Olig2 as factors required for development of striatal compartmentation and neuronal phenotypic differentiation

Abstract

The basal ganglia, best known for processing information required for multiple aspects of movement, is also part of a network which regulates reward and cognition. The major output nucleus of the basal ganglia is the striatum, and its functions are dependent on neuronal compartmentation, including striosomes and matrix, which are selectively affected in disease.Striatal projection neurons are GABAergic medium spiny neurons (MSNs), all of which share basic molecular signatures but are subtyped by selective expression of receptors, neuropeptides, and other gene families. Neurogenesis of the striosome and matrix occurs in separate waves, but the factors regulating terminal neuronal differentiation following migration are largely unidentified.We performed RNA--and ATAC--seq on sorted murine striosome and matrix cells at postnatal day 3. Focusing on the striosomal compartment, we validated the localization and role of transcription factors and their regulator(s), previously not known to be associated with striatal development, including Irx1, Foxf2, Olig2 and Stat1/2. In addition, we validated the enhancer function of a striosome--specific open chromatin region located 15Kb downstream of the Olig2 gene. These data and data bases provide novel tools to dissect and manipulate the networks regulating MSN compartmentation and differentiation and thus provide new approaches to establishing MSN subtypes from human iPSCs for disease modeling and drug discovery.

Striatal Cholinergic Dysregulation after Neonatal Decrease in X‐Linked Dystonia Parkinsonism‐Related TAF1 Isoforms

“…Striatal neurodegeneration in XDP begins in the striosomes, which comprise 10% to 15% of the striatal volume and contain both direct ( Drd1 ‐expressing) and indirect ( Drd2 ‐expressing) MSNs and are distinguished from the MSNs in the matrix by specific molecular markers 89‐96 . Although some striosome markers, for example, Irx1 , Tshz1 , Nnat , and Pdyn , 97,98 were in the lists of DEGs with adjusted or nominal P < 0.05, a clear preponderance of striosome markers or even a direction of change were not apparent, and the striosome area was unchanged. The prominence of the KEGG glutamatergic pathway may be a clue regarding neurodegeneration in XDP based on excitotoxicity and its role in HD, and the KEGG calcium signaling pathway also provides a link to apoptosis 41‐44 .…”

The genetic architecture of language functional connectivity

“…Indirect predictions might be added from the following annotation. RASGRP1, identified by chromatin interaction mapping and which also appears to be under control of temporal expression during neurodevelopment, is reported as over-expressed in the perisylvian language areas (Johnson et al, 2009) and as up-regulated in the dorsal striatum (Cirnaru et al, 2020). Fig.…”