Cranial Neural Crest Specific Deletion of <i>Alpl</i> (TNAP) via P0-Cre Causes Abnormal Chondrocyte Maturation and Deficient Cranial Base Growth
Bone growth plate abnormalities and skull shape defects are seen in hypophosphatasia, a heritable disorder in humans that occurs due to the deficiency of tissue nonspecific alkaline phosphatase (TNAP, <i>Alpl</i>) enzyme activity. The abnormal development of the cranial base growth plate...
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MDPI AG
2023-10-01
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| Series: | International Journal of Molecular Sciences |
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| author | Naoto Ohkura Hwa Kyung Nam Fei Liu Nan Hatch |
| author_facet | Naoto Ohkura Hwa Kyung Nam Fei Liu Nan Hatch |
| author_sort | Naoto Ohkura |
| collection | DOAJ |
| description | Bone growth plate abnormalities and skull shape defects are seen in hypophosphatasia, a heritable disorder in humans that occurs due to the deficiency of tissue nonspecific alkaline phosphatase (TNAP, <i>Alpl</i>) enzyme activity. The abnormal development of the cranial base growth plates (synchondroses) and abnormal skull shapes have also been demonstrated in global <i>Alpl</i><sup>−/−</sup> mice. To distinguish local vs. systemic effects of TNAP on skull development, we utilized P0-Cre to knockout <i>Alpl</i> only in cranial neural crest-derived tissues using <i>Alpl</i> flox mice. Here, we show that <i>Alpl</i> deficiency using P0-Cre in cranial neural crest leads to skull shape defects and the deficient growth of the intersphenoid synchondrosis (ISS). ISS chondrocyte abnormalities included increased proliferation in resting and proliferative zones with decreased apoptosis in hypertrophic zones. ColX expression was increased, which is indicative of premature differentiation in the absence of <i>Alpl</i>. Sox9 expression was increased in both the resting and prehypertrophic zones of mutant mice. The expression of Parathyroid hormone related protein (PTHrP) and Indian hedgehog homolog (IHH) were also increased. Finally, cranial base organ culture revealed that inorganic phosphate (P<sub>i</sub>) and pyrophosphate (PP<sub>i</sub>) have specific effects on cell signaling and phenotype changes in the ISS. Together, these results demonstrate that the TNAP expression downstream of <i>Alpl</i> in growth plate chondrocytes is essential for normal development, and that the mechanism likely involves Sox9, PTHrP, IHH and PP<sub>i</sub>. |
| first_indexed | 2024-03-10T21:11:32Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T21:11:32Z |
| publishDate | 2023-10-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-26964f2055844dcf81cb5b43dc5b7ba32023-11-19T16:46:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-10-0124201540110.3390/ijms242015401Cranial Neural Crest Specific Deletion of <i>Alpl</i> (TNAP) via P0-Cre Causes Abnormal Chondrocyte Maturation and Deficient Cranial Base GrowthNaoto Ohkura0Hwa Kyung Nam1Fei Liu2Nan Hatch3Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USADepartment of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USADepartment of Biomaterials Sciences and Prosthodontics, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USADepartment of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USABone growth plate abnormalities and skull shape defects are seen in hypophosphatasia, a heritable disorder in humans that occurs due to the deficiency of tissue nonspecific alkaline phosphatase (TNAP, <i>Alpl</i>) enzyme activity. The abnormal development of the cranial base growth plates (synchondroses) and abnormal skull shapes have also been demonstrated in global <i>Alpl</i><sup>−/−</sup> mice. To distinguish local vs. systemic effects of TNAP on skull development, we utilized P0-Cre to knockout <i>Alpl</i> only in cranial neural crest-derived tissues using <i>Alpl</i> flox mice. Here, we show that <i>Alpl</i> deficiency using P0-Cre in cranial neural crest leads to skull shape defects and the deficient growth of the intersphenoid synchondrosis (ISS). ISS chondrocyte abnormalities included increased proliferation in resting and proliferative zones with decreased apoptosis in hypertrophic zones. ColX expression was increased, which is indicative of premature differentiation in the absence of <i>Alpl</i>. Sox9 expression was increased in both the resting and prehypertrophic zones of mutant mice. The expression of Parathyroid hormone related protein (PTHrP) and Indian hedgehog homolog (IHH) were also increased. Finally, cranial base organ culture revealed that inorganic phosphate (P<sub>i</sub>) and pyrophosphate (PP<sub>i</sub>) have specific effects on cell signaling and phenotype changes in the ISS. Together, these results demonstrate that the TNAP expression downstream of <i>Alpl</i> in growth plate chondrocytes is essential for normal development, and that the mechanism likely involves Sox9, PTHrP, IHH and PP<sub>i</sub>.https://www.mdpi.com/1422-0067/24/20/15401tissue nonspecific alkaline phosphatasehypophosphatasiacranial neural crestcranial basesynchondrosischondrocyte |
| spellingShingle | Naoto Ohkura Hwa Kyung Nam Fei Liu Nan Hatch Cranial Neural Crest Specific Deletion of <i>Alpl</i> (TNAP) via P0-Cre Causes Abnormal Chondrocyte Maturation and Deficient Cranial Base Growth International Journal of Molecular Sciences tissue nonspecific alkaline phosphatase hypophosphatasia cranial neural crest cranial base synchondrosis chondrocyte |
| title | Cranial Neural Crest Specific Deletion of <i>Alpl</i> (TNAP) via P0-Cre Causes Abnormal Chondrocyte Maturation and Deficient Cranial Base Growth |
| title_full | Cranial Neural Crest Specific Deletion of <i>Alpl</i> (TNAP) via P0-Cre Causes Abnormal Chondrocyte Maturation and Deficient Cranial Base Growth |
| title_fullStr | Cranial Neural Crest Specific Deletion of <i>Alpl</i> (TNAP) via P0-Cre Causes Abnormal Chondrocyte Maturation and Deficient Cranial Base Growth |
| title_full_unstemmed | Cranial Neural Crest Specific Deletion of <i>Alpl</i> (TNAP) via P0-Cre Causes Abnormal Chondrocyte Maturation and Deficient Cranial Base Growth |
| title_short | Cranial Neural Crest Specific Deletion of <i>Alpl</i> (TNAP) via P0-Cre Causes Abnormal Chondrocyte Maturation and Deficient Cranial Base Growth |
| title_sort | cranial neural crest specific deletion of i alpl i tnap via p0 cre causes abnormal chondrocyte maturation and deficient cranial base growth |
| topic | tissue nonspecific alkaline phosphatase hypophosphatasia cranial neural crest cranial base synchondrosis chondrocyte |
| url | https://www.mdpi.com/1422-0067/24/20/15401 |
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