Disorders of Secondary Neurulation: Suggestion of a New Classification According to Pathoembryogenesis

Yang, Jeyul; Lee, Ji Yeoun; Kim, Kyung Hyun; Yang, Hee-Jong; Wang, Kyu-Chang

doi:10.1007/978-3-030-99166-1_9

Cited by 4 publications

(2 citation statements)

References 67 publications

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“…After completion of PNP closure, the NT lumen extends caudally beyond Closure 5 through a process of mesenchyme-to-epithelium transition, with lumen formation referred to as secondary neurulation, forming the sacral and coccygeal spine. Several important but poorly understood NTDs characteristically localise to the junctional region between primary and secondary neurulation, where Closure 5 forms ( Yang et al, 2022 ; Copp and Greene, 2013 ). These include terminal myelocystocele, often described as a ‘closed’ form of spina bifida because the dysmorphic spinal cord is covered with skin ( Lee et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Caudal Fgfr1 disruption produces localised spinal mis-patterning and a terminal myelocystocele-like phenotype in mice

Maniou,

Farah,

Marshall

et al. 2023

Development

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Closed spinal dysraphisms are poorly understood malformations classified as neural tube (NT) defects. Several, including terminal myelocystocele, affect the distal spine. We have previously identified a NT closure-initiating point, Closure 5, in the distal spine of mice. Here, we document equivalent morphology of the caudal-most closing posterior neuropore (PNP) in mice and humans. Closure 5 forms in a region of active FGF signalling, and pharmacological FGF receptor blockade impairs its formation in cultured mouse embryos. Conditional genetic deletion of Fgfr1 in caudal embryonic tissues with Cdx2Cre diminishes neuroepithelial proliferation, impairs Closure 5 formation and delays PNP closure. After closure, the distal NT of Fgfr1-disrupted embryos dilates to form a fluid-filled sac overlying ventrally flattened spinal cord. This phenotype resembles terminal myelocystocele. Histological analysis reveals regional and progressive loss of SHH- and FOXA2-positive ventral NT domains, resulting in OLIG2 labelling of the ventral-most NT. The OLIG2 domain is also subsequently lost, eventually producing a NT that is entirely positive for the dorsal marker PAX3. Thus, a terminal myelocystocele-like phenotype can arise after completion of NT closure with localised spinal mis-patterning caused by disruption of FGFR1 signalling.

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Section: Introductionmentioning

confidence: 99%

Caudal Fgfr1 disruption produces localised spinal mis-patterning and a terminal myelocystocele-like phenotype in mice

Maniou,

Farah,

Marshall

et al. 2023

Development

View full text Add to dashboard Cite

show abstract

“…The NT lumen extends caudally beyond Closure 5 through a process of mesenchyme-to-epithelium transition with lumen formation referred to as secondary neurulation, forming the sacral and coccygeal spine. Several important but poorly understood NTDs characteristically localise to the junctional region between primary and secondary neurulation, where Closure 5 forms (7, 8). These include terminal myelocystocele, often described as a “closed” form of spina bifida because the dysmorphic spinal cord is covered with skin (9).…”

Section: Introductionmentioning

confidence: 99%

CaudalFgfr1disruption produces localised spinal mis-patterning and a terminal myelocystocele-like phenotype in mice

Maniou

Farah

Crane-Smith

et al. 2023

Preprint

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Closed spinal dysraphisms are poorly understood neurodevelopmental malformations commonly classed as neural tube defects. Several, including terminal myelocystocele, selectively affect the distal lumbosacral spine. We previously identified a neural tube closure-initiating point, Closure 5, involved in forming the distal spine of mice. Here we document equivalent morphology of the caudal-most end of the closing posterior neuropore (PNP) in mice and humans, suggesting Closure 5 is conserved in humans. It forms in a region of active fibroblast growth factor (FGF) signalling and pharmacological blockade of FGF receptors (Fgfr) impairs Closure 5 formation in cultured mouse embryos. Conditional genetic deletion of Fgfr1 in caudal embryonic tissues with Cdx2Cre similarly impairs Closure 5 formation and leads to morphologically abnormal PNPs, which nonetheless achieve delayed closure although delayed. After PNP closure, a localised region of the distal neural tube of Fgfr1-disrupted embryos re-opens into a trumpet-like flared central canal between the presumptive hindlimbs, progressing to form a distal fluid-filled sac overlying ventrally flattened spinal cord. This phenotype resembles terminal myelocystocele. Histological analysis of spinal progenitor domains reveals regional and progressive loss of ventral spinal cord progenitor domains preceding cystic dilation of the central canal. Initially, the Shh and FoxA2-positive ventral domains are lost, resulting in Olig2-labelling of the ventral-most neural tube. The Olig2-domain is also subsequently lost, eventually producing a neural tube entirely positive for the dorsal marker Pax3. Thus, a terminal myelocystocele-like phenotype can arise after completion of neural tube closure due to localised spinal mis-patterning caused by disruption of Fgfr1 signalling.

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Sacral Agenesis

Sánchez-Romero,

Tlaxcala-Castillo,

Pichardo-Rojas

et al. 2025

Pediatric Neurology

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Disorders of Secondary Neurulation: Suggestion of a New Classification According to Pathoembryogenesis

Cited by 4 publications

References 67 publications

Caudal Fgfr1 disruption produces localised spinal mis-patterning and a terminal myelocystocele-like phenotype in mice

Caudal Fgfr1 disruption produces localised spinal mis-patterning and a terminal myelocystocele-like phenotype in mice

CaudalFgfr1disruption produces localised spinal mis-patterning and a terminal myelocystocele-like phenotype in mice

Sacral Agenesis

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