Cleft lip and palate results from Hedgehog signaling antagonism in the mouse: Phenotypic characterization and clinical implications

Lipinski, Robert J.; Song, C.; Sulik, Kathleen K.; Everson, Joshua L.; Gipp, Jerry J.; Dong, Yan; Bushman, Wade; Rowland, Ian J.

doi:10.1002/bdra.20656

Cited by 80 publications

(82 citation statements)

References 54 publications

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“…8N,O,T,U). It is established that abnormally low and high levels of Shh can also result in facial abnormalities (Lipinski et al, 2010), and the improved phenotype observed further supports the notion that the increased Shh level observed in Hand1 phospho-mutants contributes directly to the mid-face cleft phenotype.…”

Section: Inhibition Of Shh Signaling Partially Rescues Hand1 Phosphomsupporting

confidence: 58%

Hand1 phosphoregulation within the distal arch neural crest is essential for craniofacial morphogenesis

et al. 2014

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In this study we examine the consequences of altering Hand1 phosphoregulation in the developing neural crest cells (NCCs) of mice. Whereas Hand1 deletion in NCCs reveals a nonessential role for Hand1 in craniofacial development and embryonic survival, altering Hand1 phosphoregulation, and consequently Hand1 dimerization affinities, in NCCs results in severe mid-facial clefting and neonatal death. Hand1 phosphorylation mutants exhibit a noncell-autonomous increase in pharyngeal arch cell death accompanied by alterations in Fgf8 and Shh pathway expression. Together, our data indicate that the extreme distal pharyngeal arch expression domain of Hand1 defines a novel bHLH-dependent activity, and that disruption of established Hand1 dimer phosphoregulation within this domain disrupts normal craniofacial patterning.

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Section: Inhibition Of Shh Signaling Partially Rescues Hand1 Phosphomsupporting

confidence: 58%

Hand1 phosphoregulation within the distal arch neural crest is essential for craniofacial morphogenesis

et al. 2014

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“…Specifically, secretion of SHH ligand from the ectoderm activates pathway activity in the adjacent cranial neural crest-derived mesenchyme (Marcucio et al, 2005;Hu and Marcucio, 2009;Hu et al, 2015;Xavier et al, 2016). Demonstrating clinical relevance, we have shown that transient in utero exposure to the Shh pathway inhibitor cyclopamine causes lateral clefts of the lip that typically extend into the primary and secondary palate, and that this model recapitulates human non-syndromic cleft lip with or without cleft palate (CL/P) (Lipinski et al, 2008b(Lipinski et al, , 2010(Lipinski et al, , 2014. Here, we utilized this pathway-specific mouse model of cleft lip to identify and investigate the mechanism of action of Shh target genes that mediate normal and abnormal upper lip morphogenesis.…”

Section: Introductionmentioning

confidence: 61%

“…This subcutaneous infusion exposure model yields steady-state serum concentrations within a few hours after pump implantation (GD8.25) that persist until dispensation is complete (∼GD9.375) (Lipinski et al, 2008b(Lipinski et al, , 2010.…”

Section: Cyclopamine Administrationmentioning

confidence: 99%

Sonic Hedgehog regulation of Foxf2 promotes cranial neural crest mesenchyme proliferation and is disrupted in cleft lip morphogenesis

et al. 2017

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Cleft lip is one of the most common human birth defects, yet our understanding of the mechanisms that regulate lip morphogenesis is limited. Here, we show in mice that sonic hedgehog (Shh)-induced proliferation of cranial neural crest cell (cNCC) mesenchyme is required for upper lip closure. Gene expression profiling revealed a subset of Forkhead box (Fox) genes that are regulated by Shh signaling during lip morphogenesis. During cleft pathogenesis, reduced proliferation in the medial nasal process mesenchyme paralleled the domain of reduced Foxf2 and Gli1 expression. SHH ligand induction of Foxf2 expression was dependent upon Shh pathway effectors in cNCCs, while a functional GLI-binding site was identified downstream of Foxf2. Consistent with the cellular mechanism demonstrated for cleft lip pathogenesis, we found that either SHH ligand addition or FOXF2 overexpression is sufficient to induce cNCC proliferation. Finally, analysis of a large multi-ethnic human population with cleft lip identified clusters of single-nucleotide polymorphisms in FOXF2. These data suggest that direct targeting of Foxf2 by Shh signaling drives cNCC mesenchyme proliferation during upper lip morphogenesis, and that disruption of this sequence results in cleft lip.

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“…Finally, the anterior and intermediate lobes of the pituitary gland derive from the oral ectodermal placode, while the posterior pituitary is derived from the neural ectoderm. A recent study in mice showed that anterior pituitary is indeed majorly affected in those with orofacial clefts (34). To act on this knowledge, the type and severity of orofacial clefts may be considered to be parallel to the accompanying pituitary defects.…”

Section: Discussionmentioning

confidence: 99%

Endocrine abnormalities of patients with cleft lip and/or cleft palate during the neonatal period

Akın¹,

Kurtoğlu²,

Sarıcı³

et al. 2014

Turk J Med Sci

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IntroductionCultivated strawberry, Fragaria × ananassa, is the natural hybrid of F. chiloensis and F. virginiana and is thought to be only about 300 years old (Hancock, 1999). Earlier researchers have reported that the cultivated strawberry has very narrow genetic diversity when compared with its progenitor species (Dale and Sjulin, 1990;Hancock, 2006;Horvath et al., 2011). Since the progenitor species can easily be crossed with the cultivated strawberry, several attempts have been made to utilize the wild species to expand the genetic base of cultivated strawberry. An example of successful utilization of the wild species includes the introgression of day-neutrality from F. virginiana subsp.

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Cleft lip and palate results from Hedgehog signaling antagonism in the mouse: Phenotypic characterization and clinical implications

Cited by 80 publications

References 54 publications

Hand1 phosphoregulation within the distal arch neural crest is essential for craniofacial morphogenesis

Hand1 phosphoregulation within the distal arch neural crest is essential for craniofacial morphogenesis

Sonic Hedgehog regulation of Foxf2 promotes cranial neural crest mesenchyme proliferation and is disrupted in cleft lip morphogenesis

Endocrine abnormalities of patients with cleft lip and/or cleft palate during the neonatal period

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