Experimental Aspects of the Pathogenesis of Robin Sequence

Schubert, Johannes; Jahn, Heiko J.; Berginski, Markus

doi:10.1597/03-166.1

Cited by 21 publications

(18 citation statements)

References 17 publications

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“…Children with FD can exhibit retrognathism of the mandible and a resulting reduced inferior facial angle (24). Because the Wnt1 + cranial crest orchestrates and contributes to much of the cranial facial morphology (23), we measured the inferior facial angle and the position of the mandible relative to the most anterior point on the face (25) (Fig. S2 C and D).…”

Section: Resultsmentioning

confidence: 99%

Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3 ⁺ progenitors and peripheral neurons

George

Chaverra

Wolfe

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

159

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Familial dysautonomia (FD) is a devastating developmental and progressive peripheral neuropathy caused by a mutation in the gene inhibitor of kappa B kinase complex-associated protein (IKBKAP). To identify the cellular and molecular mechanisms that cause FD, we generated mice in which Ikbkap expression is ablated in the peripheral nervous system and identify the steps in peripheral nervous system development that are Ikbkap-dependent. We show that Ikbkap is not required for trunk neural crest migration or pathfinding, nor for the formation of dorsal root or sympathetic ganglia, or the adrenal medulla. Instead, Ikbkap is essential for the second wave of neurogenesis during which the majority of tropomyosin-related kinase A (TrkA + ) nociceptors and thermoreceptors arise. In its absence, approximately half the normal complement of TrkA + neurons are lost, which we show is partly due to p53-mediated premature differentiation and death of mitotically-active progenitors that express the paired-box gene Pax3 and give rise to the majority of TrkA + neurons. By the end of sensory development, the number of TrkC neurons is significantly increased, which may result from an increase in Runx3 + cells. Furthermore, our data demonstrate that TrkA + (but not TrkC + ) sensory and sympathetic neurons undergo exacerbated Caspase 3-mediated programmed cell death in the absence of Ikbkap and that this death is not due to a reduction in nerve growth factor synthesis. In summary, these data suggest that FD does not result from a failure in trunk neural crest migration, but rather from a critical function for Ikbkap in TrkA progenitors and TrkA + neurons.H ereditary sensory and autonomic neuropathies (HSANs) are a group of five phenotypically diverse but overlapping disorders of the peripheral nervous system (PNS) that result from mutations in 12 distinct genes (1). HSAN type 3, or familial dysautonomia (FD) (also called Riley-Day syndrome), results from an intronic mutation (IVS20 + 6T > C; 99.5% of patients) in a gene called inhibitor of kappa B kinase complex-associated protein or IKBKAP, causing mis-splicing and subsequent tissuespecific reductions in IKAP protein (2, 3). FD is marked by tachycardia, blood pressure lability, autonomic vomiting "crises," decreased pain and temperature sensation, and commonly death during early adulthood (4). The function of IKAP in the nervous system is unclear, nor is it understood why deletions in this broadly expressed gene primarily devastate the PNS. The earliest pathology study, performed on a 2-y-old child with FD, showed that ∼90% of cells in the dorsal root and sympathetic ganglia (SG) were missing (5). To identify IKAP's function in the developing PNS, we first need to establish the steps in which it is essential.The vertebrate PNS derives primarily from the neural crest, a multipotent, heterogeneous cell population that delaminates from the neural tube and migrates throughout the embryo (6). Those neural crest cells that stop laterally to the neural tube give rise to the chain of sensory...

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Section: Resultsmentioning

confidence: 99%

Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3 ⁺ progenitors and peripheral neurons

George

Chaverra

Wolfe

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

159

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“…This model is supported by analyses of two mouse models of Pierre Robin Sequence, the A/WySn inbred mouse strain (Schubert et al, 2005) and mice heterozygous for the disproportionate micromelia (Dmm) mutation (Ricks et al, 2002), a semidominant mutant allele of the Col2a1 gene (Pace et al, 1997). Based on a mechanical requirement for mandibular extension to drive the proper depression of the tongue, we propose that a similar mechanism is responsible for the cleft palate phenotype of Snai1/2-dko mice.…”

Section: Snai1/2-dko Embryos As a Model For Pierre Robin Sequencementioning

confidence: 95%

Multiple functions of Snail family genes during palate development in mice

2007

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Palate development requires precise regulation of gene expression changes,morphogenetic movements and alterations in cell physiology. Defects in any of these processes can result in cleft palate, a common human birth defect. The Snail gene family encodes transcriptional repressors that play essential roles in the growth and patterning of vertebrate embryos. Here we report the functions of Snail (Snai1) and Slug (Snai2) genes during palate development in mice. Snai2-/- mice exhibit cleft palate, which is completely penetrant on a Snai1 heterozygous genetic background. Cleft palate in Snai1+/- Snai2-/-embryos is due to a failure of the elevated palatal shelves to fuse. Furthermore, while tissue-specific deletion of the Snai1 gene in neural crest cells does not cause any obvious defects, neural-crest-specific Snai1 deletion on a Snai2-/- genetic background results in multiple craniofacial defects, including a cleft palate phenotype distinct from that observed in Snai1+/-Snai2-/- embryos. In embryos with neural-crest-specific Snai1 deletion on a Snai2-/- background, palatal clefting results from a failure of Meckel's cartilage to extend the mandible and thereby allow the palatal shelves to elevate, defects similar to those seen in the Pierre Robin Sequence in humans.

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“…The nose, maxilla and mandible form early during human embyrogenesis with large contributions from lateral plate mesoderm and from neural crest (7)(8)(9)(10)(11). The nasal placodes give rise to nasal development around the fifth week.…”

mentioning

confidence: 99%

“…Interruption of any of these processes leads to craniofacial anomalies and secondarily affects the upper aerodigestive tract. The growth of the craniofacial skeleton is impacted by the functional status of each sub-component, and the coordinated adjustment of all tissues (7,8,10).…”

mentioning

confidence: 99%

“…For example, in Pierre-Robin sequence (PRS), differentiation of tongue musculature is thought to be delayed. The reduced muscular activity associated with delayed tongue development then results in decreased mandibular growth and a failure of the palatal shelves to rotate properly, leading to a palatal cleft (10). Therefore, studies have shown a correlation between mandible length and severity of the palatal cleft in PRS (7).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Developmental Aspects of the Upper Airway: Report from an NHLBI Workshop, March 5-6, 2009

Marcus¹,

Smith²,

Mankarious³

et al. 2009

Proceedings of the American Thoracic Society

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Experimental Aspects of the Pathogenesis of Robin Sequence

Abstract: The results support the primary role of retroposition of the mandible in the development of cardinal symptoms of Pierre Robin Sequence.

Cited by 21 publications

References 17 publications

Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3 ⁺ progenitors and peripheral neurons

Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3 ⁺ progenitors and peripheral neurons

Multiple functions of Snail family genes during palate development in mice

Developmental Aspects of the Upper Airway: Report from an NHLBI Workshop, March 5-6, 2009

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Experimental Aspects of the Pathogenesis of Robin Sequence

Abstract: The results support the primary role of retroposition of the mandible in the development of cardinal symptoms of Pierre Robin Sequence.

Cited by 21 publications

References 17 publications

Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3 + progenitors and peripheral neurons

Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3 + progenitors and peripheral neurons

Multiple functions of Snail family genes during palate development in mice

Developmental Aspects of the Upper Airway: Report from an NHLBI Workshop, March 5-6, 2009

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Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3 ⁺ progenitors and peripheral neurons

Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3 ⁺ progenitors and peripheral neurons