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.
Highlights
Proper development of the cerebral cortex and commissures is achieved by a long and controlled process of proliferation, differentiation, migration, and organization of neuronal and glial cells (Marin and Rubenstein, 2001; Schuurmans and Guillemot, 2002; Mochida and Walsh, 2004; Barkovich et al, 2005; Guillemot et al, 2006; Guerrini and Parrini, 2010)
Using a well-characterized antibody generating little to no non-specific reactivity (H12), we have shown that HCF-1 is ubiquitous and predominantly nuclear in E6.5-to-E12.5 embryos, postnatal day 0 (P0) brains, and 10-week-old young adult brains (Minocha et al, 2016b)
We focused on the cortex (Ctx), corpus callosum (CC), and anterior commissure (AC) — brain regions affected by the Nkx2.1-Cre-engineered loss of HCF-1 described here
Summary
Proper development of the cerebral cortex and commissures is achieved by a long and controlled process of proliferation, differentiation, migration, and organization of neuronal and glial cells (Marin and Rubenstein, 2001; Schuurmans and Guillemot, 2002; Mochida and Walsh, 2004; Barkovich et al, 2005; Guillemot et al, 2006; Guerrini and Parrini, 2010). We study the role of the X-linked Hcfc gene in these processes. Genetic studies in mammalian cell culture, early mouse embryos, and liver have shown that HCF-1 is important for multiple aspects of cell proliferation (Goto et al, 1997; Reilly and Herr, 2002; Julien and Herr, 2003; Minocha et al, 2016b), and very early epiblast-specific embryonic loss of HCF-1 is lethal before gastrulation (Minocha et al, 2016a; 2016b). In humans, there are mutations in the HCFC1 gene that are associated with X-linked intellectual disability (ID) and cobalamin metabolism; these disorders point toward an important role of HCF-1 in brain development (Huang et al, 2012; Yu et al, 2013; Gerard et al, 2015; Jolly et al, 2015; Koufaris et al, 2016). Reduced migration of GABAergic interneurons and glia was accompanied with corpus callosum defects and abnormal formation of the anterior commissure as well as severe cortical defects that resembled polymicrogyria
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