Cortical and Commissural Defects Upon HCF‐1 Loss in Nkx2.1‐Derived Embryonic Neurons and Glia

Abstract

Formation of the cerebral cortex and commissures involves a complex developmental process defined by multiple molecular mechanisms governing proliferation of neuronal and glial precursors, neuronal and glial migration, and patterning events. Failure in any of these processes can lead to malformations. Here, we study the role of HCF‐1 in these processes. HCF‐1 is a conserved metazoan transcriptional co‐regulator long implicated in cell proliferation and more recently in human metabolic disorders and mental retardation. Loss of HCF‐1 in a subset of ventral telencephalic Nkx2.1‐positive progenitors leads to reduced numbers of GABAergic interneurons and glia, owing not to decreased proliferation but rather to increased apoptosis before cell migration. The loss of these cells leads to development of severe commissural and cortical defects in early postnatal mouse brains. These defects include mild and severe structural defects of the corpus callosum and anterior commissure, respectively, and increased folding of the cortex resembling polymicrogyria. Hence, in addition to its well‐established role in cell proliferation, HCF‐1 is important for organ development, here the brain.

Role of Specialized Composition of SWI/SNF Complexes in Prostate Cancer Lineage Plasticity

“…In particular, SWI/SNF interacts with the transcription factor NK2 homeobox 1 (NKX2.1/TTF-1) in CRPC-NE cells, but not in adenocarcinoma cells. TTF-1 is a master regulator critical for the development of lung and thyroid, but also of specific parts of the brain [78][79][80] and is known to be expressed in neuroendocrine tumors, including CRPC-NE 81 , which is consistent with our data ( Fig.4c, 4d). We also observed SWI/SNF interaction with Metastasis-associated Protein 1 (MTA1), a member of the nucleosome-remodeling and deacetylation complex (NuRD), which is overexpressed in metastatic prostate cancer 82 , in some types of neuroendocrine tumors 83 and in a subset of CRPC-NE cell lines/organoids in our study (Fig.…”

Hcfc1a regulates neural precursor proliferation and asxl1 expression in the developing brain.

“…The resulting approach introduces the formation of a truncated protein, whereas, our system results in decreased overall expression ( Figure 1) more consistent with previous in vitro assays and haploinsufficiency. However our haploinsufficient allele advances the field because unlike the previous in vitro assays (14,15), our allele accounts for the broad expression of Hcfc1 which was recently documented by Minocha and colleagues (17).…”

“…Here we developed a zebrafish harboring a germline mutation in the hcfc1a gene. We analyzed the expression are yet to be elucidated, however studies that provide information on brain volume and the ratio of gray and white matter in the central nervous system are warranted given that the increases in neurons and glia we observed are unique from the differentiation defects observed in previous studies (14,17). However, we suspect the difference in phenotype is associated with the type of mutation introduced, the brain microenvironment, the cell population analyzed, and the region of the brain of interest.…”

“…Previous studies suggest that HCFC1 regulates NPC function in vitro and in mouse models (14)(15)(16)(17).…”

“…Previous studies have demonstrated a complex network of transcription factors that are responsible for modulating NPC function including SOX2 (8), SOX1 (9), NESTIN (10), and PAX transcription factors (11). Recent evidence suggests that the HCFC1 gene, which encodes a transcriptional cofactor, is essential for stem cell proliferation and metabolism (12,13) in a variety of different tissue types, including neural precursors (14)(15)(16)(17). These data strongly suggest that HCFC1 is part of a more global transcriptional program modulating NPC proliferation and differentiation.…”