Roof plate mediated morphogenesis of the forebrain: New players join the game

Gupta, Sandeep; Sen, Jonaki

doi:10.1016/j.ydbio.2016.03.019

Cited by 8 publications

(6 citation statements)

References 90 publications

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“…In the developing CNS, SHH is secreted by the notochord and floor plate and forms a ventral to dorsal gradient that regulates diverse essential processes such as specification of ventral fate, proliferation, and axonal guidance. 1,2 Similarly, SHH orchestrates several aspects of cerebellar development, initially stimulating the proliferation of cerebellar progenitors in the rhombic lip and the ventricular zone, and later that of granule cell precursors in the external granular layer. 3,4 During formation of the limb skeleton, SHH is required for the survival and expansion of distal chondrogenic progenitor cells and for specification of digit identities along the anterior-posterior axis.…”

Section: Introductionmentioning

confidence: 99%

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

Mori

Romani²,

D’Arrigo

et al. 2017

The American Journal of Human Genetics

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The Sonic Hedgehog (SHH) pathway is a key signaling pathway orchestrating embryonic development, mainly of the CNS and limbs. In vertebrates, SHH signaling is mediated by the primary cilium, and genetic defects affecting either SHH pathway members or ciliary proteins cause a spectrum of developmental disorders. SUFU is the main negative regulator of the SHH pathway and is essential during development. Indeed, Sufu knock-out is lethal in mice, and recessive pathogenic variants of this gene have never been reported in humans. Through whole-exome sequencing in subjects with Joubert syndrome, we identified four children from two unrelated families carrying homozygous missense variants in SUFU. The children presented congenital ataxia and cerebellar vermis hypoplasia with elongated superior cerebellar peduncles (mild ''molar tooth sign''), typical cranio-facial dysmorphisms (hypertelorism, depressed nasal bridge, frontal bossing), and postaxial polydactyly. Two siblings also showed polymicrogyria. Molecular dynamics simulation predicted random movements of the mutated residues, with loss of the native enveloping movement of the binding site around its ligand GLI3. Functional studies on cellular models and fibroblasts showed that both variants significantly reduced SUFU stability and its capacity to bind GLI3 and promote its cleavage into the repressor form GLI3R. In turn, this impaired SUFU-mediated repression of the SHH pathway, as shown by altered expression levels of several target genes. We demonstrate that germline hypomorphic variants of SUFU cause deregulation of SHH signaling, resulting in recessive developmental defects of the CNS and limbs which share features with both SHH-related disorders and ciliopathies.

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Section: Introductionmentioning

confidence: 99%

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

Mori

Romani²,

D’Arrigo

et al. 2017

The American Journal of Human Genetics

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“…Together, these data support a key role for Zic2, together with Glis, Six3 and FoxG1, in integrating inputs from the three forebrain organizers. These molecules comprise a regulatory network that is crucial for forebrain development, but remains poorly understood . Understanding the role (or roles) of Zic2 in the network will also help solve one of the remaining puzzles in HPE, namely, why so few of the genetic risk factors identified in mammals affect formation of the telencephalic roof plate, the actual site of hemispheric separation.…”

Section: Dorsoventral Pattern In the Forebrain Primordiummentioning

confidence: 99%

“…These molecules comprise a regulatory network that is crucial for forebrain development, but remains poorly understood. 54,55 Understanding the role (or roles) of Zic2 in the network will also help solve one of the remaining puzzles in HPE, namely, why so few of the genetic risk factors identified in mammals affect formation of the telencephalic roof plate, the actual site of hemispheric separation. The isoform of HPE that presents with dorsal deficits is termed midline inter-hemispheric (MIH) HPE, in contrast to classic HPE, characterized by ventral midline defects.…”

Section: Dorsoventral Pattern In the Forebrain Primordiummentioning

confidence: 99%

A forebrain undivided: Unleashing model organisms to solve the mysteries of holoprosencephaly

Grinblat

Lipinski

2019

Developmental Dynamics

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Evolutionary conservation and experimental tractability have made animal model systems invaluable tools in our quest to understand human embryogenesis, both normal and abnormal. Standard genetic approaches, particularly useful in understanding monogenic diseases, are no longer sufficient as research attention shifts toward multifactorial outcomes. Here, we examine this progression through the lens of holoprosencephaly (HPE), a common human malformation involving incomplete forebrain division, and a classic example of an etiologically complex outcome. We relate the basic underpinning of HPE pathogenesis to critical cell‐cell interactions and signaling molecules discovered through embryological and genetic approaches in multiple model organisms, and discuss the role of the mouse model in functional examination of HPE‐linked genes. We then outline the most critical remaining gaps to understanding human HPE, including the conundrum of incomplete penetrance/expressivity and the role of gene‐environment interactions. To tackle these challenges, we outline a strategy that leverages new and emerging technologies in multiple model systems to solve the puzzle of HPE.

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“…The initial stages of D-V patterning are controlled by secreted morphogenetic signals (morphogens) that spread over various distances. The combination of the activities of different morphogens gives rise to distinct expression patterns of region-specific transcription factors in the telencephalon (Gupta and Sen, 2016; Harrison-Uy and Pleasure, 2012; Lupo et al, 2006; Sur and Rubenstein, 2005), as is also the case in the vertebrate spinal cord (Andrews et al, 2019) and in invertebrate embryos (Briscoe and Small, 2015). Bone morphogenetic proteins (BMPs), Wnt ligands, Sonic hedgehog (Shh), and fibroblast growth factor 8 (FGF8) are among the morphogens involved in D-V patterning in the mammalian telencephalon.…”

Section: Introductionmentioning

confidence: 98%

The Polycomb group protein Ring1 regulates dorsoventral patterning of the mouse telencephalon

Eto

Kishi

Koseki

et al. 2019

Preprint

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SummaryPatterning of the dorsal-ventral (D-V) axis of the mammalian telencephalon is fundamental to the formation of distinct functional regions including the neocortex and ganglionic eminences. Morphogenetic signaling by bone morphogenetic protein (BMP), Wnt, Sonic hedgehog (Shh), and fibroblast growth factor (FGF) pathways determines regional identity along this axis. It has remained unclear, however, how region-specific expression patterns of these morphogens along the D-V axis are established, especially at the level of epigenetic (chromatin) regulation. Here we show that epigenetic regulation by Ring1, an essential Polycomb group (PcG) protein, plays a key role in formation of ventral identity in the mouse telencephalon. Deletion of the Ring1b or both Ring1a and Ring1b genes in neuroepithelial cells of the mouse embryo attenuated expression of the gene for Shh, a key morphogen for induction of ventral identity, and induced misexpression of dorsal marker genes including those for BMP and Wnt ligands in the ventral telencephalon. PcG protein–mediated trimethylation of histone H3 on lysine-27 (H3K27me3) was also apparent at BMP and Wnt ligand genes in wild-type embryos. Importantly, forced activation of Wnt or BMP signaling repressed the expression of Shh in organotypic and dissociated cultures of the early-stage telencephalon. Our results thus indicate that epigenetic regulation by PcG proteins—and, in particular, that by Ring1— confers a permissive state for the induction of Shh expression through suppression of BMP and Wnt signaling pathways, which in turn allows the development of ventral identity in the telencephalon.

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Roof plate mediated morphogenesis of the forebrain: New players join the game

Cited by 8 publications

References 90 publications

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

A forebrain undivided: Unleashing model organisms to solve the mysteries of holoprosencephaly

The Polycomb group protein Ring1 regulates dorsoventral patterning of the mouse telencephalon

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