NODAL and SHH dose-dependent double inhibition promotes an HPE-like phenotype in chick embryos

Mercier, Sandra; David, Véronique; Ratié, Leslie; Gicquel, Isabelle; Odent, Sylvie; Dupé, Valérie

doi:10.1242/dev.094763

Cited by 4 publications

(7 citation statements)

References 41 publications

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“…The important and wide variability of expression from an asymptomatic to severe form for a same mutation, the incomplete penetrance and the identification of several mutations in the same patient argue for this oligogenic inheritance. Furthermore, the description of numerous mouse models carrying mutations in two genes of the same or different signaling pathways involved in forebrain development strongly support this mode of inheritance by showing that a cumulative partial inhibition of signaling pathways is necessary to develop HPE [Allen et al, 2007;Krauss, 2007;Mercier et al, 2013]. However, only a few examples of digenic inheritance in human were reported in the literature until now [Nanni et al, 1999;Ming and Muenke, 2002;Lacbawan et al, 2009;Hong et al, 2016;Mouden et al, 2016].…”

Section: Discussionmentioning

confidence: 95%

“…Among them, polygenic inheritance would require two or more events involving genes from the same or different signaling pathways with functional relationship. This polygenic inheritance plays a role in the variability of the phenotype, especially when there is a functional relationship between mutated genes, as this is the case for HPE genes [Mercier et al, 2013]. This has significant implications for genetic counseling and for risk assessment of patient relatives.…”

Section: Introductionmentioning

confidence: 99%

“…Isolated HPE presents a high genetic heterogeneity. To date, heterozygous mutations in 15 genes have been identified in HPE patients with four major genes (Sonic hedgehog or SHH: MIM# 600725; ZIC2: MIM#603073; SIX3: MIM# 603714; TGIF1: MIM# 602630), and 11 genes that are considered as minor genes These genes encode proteins playing a role in early brain development, which mostly belong to the signaling pathway Shh, and to a lesser extent Nodal and Fgf pathways [Arauz et al, 2010;Mercier et al, 2013]. Mutations in SHH, SIX3, and TGIF1 are inherited from an unaffected parent or parent harboring only a microform of HPE in 70% of the cases .…”

Section: Introductionmentioning

confidence: 99%

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Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway

et al. 2016

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Holoprosencephaly (HPE) is the most common congenital cerebral malformation in humans, characterized by impaired forebrain cleavage and midline facial anomalies. It presents a high heterogeneity, both in clinics and genetics. We have developed a novel targeted next-generation sequencing (NGS) assay and screened a cohort of 257 HPE patients. Mutations with high confidence in their deleterious effect were identified in approximately 24% of the cases and were held for diagnosis, whereas variants of uncertain significance were identified in 10% of cases. This study provides a new classification of genes that are involved in HPE. SHH, ZIC2, and SIX3 remain the top genes in term of frequency with GLI2, and are followed by FGF8 and FGFR1. The three minor HPE genes identified by our study are DLL1, DISP1, and SUFU. Here, we demonstrate that fibroblast growth factor signaling must now be considered a major pathway involved in HPE. Interestingly, several cases of double mutations were found and argue for a polygenic inheritance of HPE. Altogether, it supports that the implementation of NGS in HPE diagnosis is required to improve genetic counseling.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway

et al. 2016

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“…For example, although Gas1 −/− mutant mice exhibit partial fusion of the medial nasal processes and Shh +/− mice appear normal, Gas1 −/− ; Shh +/− mice embryos display complete fusion of the medial nasal processes (21), reminiscent of a HPE phenotype. Such examples of animal models are numerous and all support the hypothesis that HPE could be because of a cumulative partial inhibition of signalling pathways implicated in forebrain development (6,22).…”

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confidence: 91%

Complex mode of inheritance in holoprosencephaly revealed by whole exome sequencing

et al. 2016

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Holoprosencephaly (HPE) is the most common congenital cerebral malformation, characterized by impaired forebrain cleavage and midline facial anomalies. Heterozygous mutations in 14 genes have been associated with HPE and are often inherited from an unaffected parent, underlying complex genetic bases. It is now emerging that HPE may result from a combination of multiple genetic events, rather than from a single heterozygous mutation. To explore this hypothesis, we undertook whole exome sequencing and targeted high-throughput sequencing approaches to identify mutations in HPE subjects. Here, we report two HPE families in which two mutations are implicated in the disease. In the first family presenting two foetuses with alobar and semi-lobar HPE, we found mutations in two genes involved in HPE, SHH and DISP1, inherited respectively from the father and the mother. The second reported case is a family with a 9-year-old girl presenting lobar HPE, harbouring two compound heterozygous mutations in DISP1. Together, these cases of digenic inheritance and autosomal recessive HPE suggest that in some families, several genetic events are necessary to cause HPE. This study highlights the complexity of HPE inheritance and has to be taken into account by clinicians to improve HPE genetic counselling.

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“…The PM expresses the secreted glycoprotein, Shh, and studies of isolated chick tissue explants reveal that Shh is required to induce Shh +ive RDVM cells. 13,15 Other factors, however, synergise with Shh to mediate this event, including the transforming growth factor β signalling ligand, Nodal, deriving from the PM 15,19,20 and the transcription factor (TF), Six3. 16 In Shh-null embryos, embryos haploinsufficient for Six3, or with dysfunctional Nodal signalling, RDVM cells are not induced and embryos develop holoprosencephalic phenotypes 16,21 .…”

Section: Induction Of Shh +Ive Ventral Midline Cellsmentioning

confidence: 99%

Development of the basal hypothalamus through anisotropic growth

Pearson

Towers

et al. 2019

J Neuroendocrinology

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The adult hypothalamus is subdivided into distinct domains: pre‐optic, anterior, tuberal and mammillary. Each domain harbours an array of neurones that act together to regulate homeostasis. The embryonic origins and the development of hypothalamic neurones, however, remain enigmatic. Here, we summarise recent studies in model organisms that challenge current views of hypothalamic development, which traditionally have attempted to map adult domains to correspondingly located embryonic domains. Instead, new studies indicate that hypothalamic neurones arise from progenitor cells that undergo anisotropic growth, expanding to a greater extent than other progenitors, and grow in different dimensions. We describe in particular how a multipotent Shh / Fgf10 ‐expressing progenitor population gives rise to progenitors throughout the basal hypothalamus that grow anisotropically and sequentially: first, a subset displaced rostrally give rise to anterior‐ventral/tuberal neuronal progenitors; then a subset displaced caudally give rise to mammillary neuronal progenitors; and, finally, a subset(s) displaced ventrally give rise to tuberal infundibular glial progenitors. As this occurs, stable populations of Shh +ive and Fgf10 +ive progenitors form. We describe current understanding of the mechanisms that induce Shh +ive /Fgf10 +ive progenitors and begin to direct their differentiation to anterior‐ventral/tuberal neuronal progenitors, mammillary neuronal progenitors and tuberal infundibular progenitors. Taken together, these studies suggest a new model for hypothalamic development that we term the “anisotropic growth model”. We discuss the implications of the model for understanding the origins of adult hypothalamic neurones.

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NODAL and SHH dose-dependent double inhibition promotes an HPE-like phenotype in chick embryos

Cited by 4 publications

References 41 publications

Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway

Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway

Complex mode of inheritance in holoprosencephaly revealed by whole exome sequencing

Development of the basal hypothalamus through anisotropic growth

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