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Homeobox genes Gsx1 and Gsx2 differentially regulate telencephalic progenitor maturation.

ABSTRACT: Homeobox genes Gsx1 and Gsx2 (formerly Gsh1 and Gsh2) are among the earliest transcription factors expressed in neuronal progenitors of the lateral ganglionic eminence (LGE) in the ventral telencephalon. Gsx2 is required for the early specification of LGE progenitor cells and recently has been shown to specify different LGE neuronal subtypes at distinct time points. In Gsx2 mutants, Gsx1 compensates, at least in part, for the loss of Gsx2 in the specification of LGE neuronal subtypes. Because no specific phenotype has been described in Gsx1 mutants, it is unclear what role this factor plays in the development of the ventral telencephalon. Here, we used a gain-of-function approach to express either Gsx1 or Gsx2 throughout the telencephalon and found that Gsx1 functions similarly to Gsx2 in the specification of LGE identity. However, our results show that Gsx1 and Gsx2 differentially regulate the maturation of LGE progenitors. Specifically, Gsx2 maintains LGE progenitors in an undifferentiated state, whereas Gsx1 promotes progenitor maturation and the acquisition of neuronal phenotypes, at least in part, through the down-regulation of Gsx2. These unique results indicate that the two closely related Gsx genes similarly regulate LGE patterning but oppositely control the balance between proliferation and differentiation in the neuronal progenitor pool.

SUBMITTER: Pei Z

PROVIDER: S-EPMC3029701 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Homeobox genes Gsx1 and Gsx2 differentially regulate telencephalic progenitor maturation.

Pei Zhenglei Z Wang Bei B Chen Gang G Nagao Motoshi M Nakafuku Masato M Campbell Kenneth K

Proceedings of the National Academy of Sciences of the United States of America 20110104 4

Homeobox genes Gsx1 and Gsx2 (formerly Gsh1 and Gsh2) are among the earliest transcription factors expressed in neuronal progenitors of the lateral ganglionic eminence (LGE) in the ventral telencephalon. Gsx2 is required for the early specification of LGE progenitor cells and recently has been shown to specify different LGE neuronal subtypes at distinct time points. In Gsx2 mutants, Gsx1 compensates, at least in part, for the loss of Gsx2 in the specification of LGE neuronal subtypes. Because no ...[more]

PMID: 21205889

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Project description:Basal ganglia are subcortical grey nuclei that play essential roles in controlling voluntary movements, cognition and emotion. While basal ganglia dysfunction is observed in many neurodegenerative or metabolic disorders, congenital malformations are rare. In particular, dysplastic basal ganglia are part of the malformative spectrum of tubulinopathies and X-linked lissencephaly with abnormal genitalia, but neurodevelopmental syndromes characterized by basal ganglia agenesis are not known to date. We ascertained two unrelated children (both female) presenting with spastic tetraparesis, severe generalized dystonia and intellectual impairment, sharing a unique brain malformation characterized by agenesis of putamina and globi pallidi, dysgenesis of the caudate nuclei, olfactory bulbs hypoplasia, and anomaly of the diencephalic-mesencephalic junction with abnormal corticospinal tract course. Whole-exome sequencing identified two novel homozygous variants, c.26C>A; p.(S9*) and c.752A>G; p.(Q251R) in the GSX2 gene, a member of the family of homeobox transcription factors, which are key regulators of embryonic development. GSX2 is highly expressed in neural progenitors of the lateral and median ganglionic eminences, two protrusions of the ventral telencephalon from which the basal ganglia and olfactory tubercles originate, where it promotes neurogenesis while negatively regulating oligodendrogenesis. The truncating variant resulted in complete loss of protein expression, while the missense variant affected a highly conserved residue of the homeobox domain, was consistently predicted as pathogenic by bioinformatic tools, resulted in reduced protein expression and caused impaired structural stability of the homeobox domain and weaker interaction with DNA according to molecular dynamic simulations. Moreover, the nuclear localization of the mutant protein in transfected cells was significantly reduced compared to the wild-type protein. Expression studies on both patients' fibroblasts demonstrated reduced expression of GSX2 itself, likely due to altered transcriptional self-regulation, as well as significant expression changes of related genes such as ASCL1 and PAX6. Whole transcriptome analysis revealed a global deregulation in genes implicated in apoptosis and immunity, two broad pathways known to be involved in brain development. This is the first report of the clinical phenotype and molecular basis associated to basal ganglia agenesis in humans.

Dataset Information

Homeobox genes Gsx1 and Gsx2 differentially regulate telencephalic progenitor maturation.

Publications

Homeobox genes Gsx1 and Gsx2 differentially regulate telencephalic progenitor maturation.

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