Mouse H6 Homeobox 1 (Hmx1) mutations cause cranial abnormalities and reduced body mass

Munroe, Robert J.; Prabhu, Vinay; Acland, Greg M.; Johnson, Kenneth R.; Harris, Belinda S.; O’Brien, Timothy; Welsh, Ian; Noden, Drew M.; Schimenti, John C.

doi:10.1186/1471-213x-9-27

Cited by 54 publications

(54 citation statements)

References 22 publications

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“…Mendelian transmission of the dumbo allele was observed between embryonic day (E) 10.5 and E14.5 (42 Hmx1 +/+ , 105 Hmx1 +/dm and 37 Hmx1 dm/dm embryos; χ 2 P=0.1391). However, similar to the previous study on a mixed genetic background (Munroe et al, 2009) mice (31.4%, 55.1% and 13.5%, respectively; χ 2 P=0.0029), suggesting ∼57% perinatal lethality of homozygous mutants, which appeared to be equally distributed between the sexes. In contrast to the earlier report (Munroe et al, 2009), only postweaning Hmx1 dm/dm male mice showed a significant reduction in weight, on average ∼23% lighter than controls (control: 17.28± 0.494 g, Hmx1 dm/dm : 13.29±1.102 g).…”

Section: Hmx1 Mutant Mice Exhibit Craniofacial and Cranioskeletal Anosupporting

confidence: 64%

“…S1A-D′). This may represent a mild neural tube defect related to the exencephaly previously documented on the mixed background (Munroe et al, 2009) and might contribute to the occasional perinatal lethality of homozygous mutant embryos.…”

Section: Hmx1 Mutant Mice Exhibit Craniofacial and Cranioskeletal Anomentioning

confidence: 99%

“…Patients with mutations in HOXA2 display severe microtia, middle ear deformities and hearing loss (Alasti et al, 2008). By contrast, OAS patients and dumbo mice have dysmorphic external ears but the middle ear and hearing appear to be unaffected (Schorderet et al, 2008;Munroe et al, 2009;Gillespie et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…This condition has been termed oculo-auricular syndrome (OAS) in humans (Schorderet et al, 2008;Gillespie et al, 2015), 'dumbo' and/or 'misplaced ears' in mice, 'dumbo' in rats (Munroe et al, 2009;Kuramoto et al, 2010;Quina et al, 2012a), and 'crop ear' in cattle (Koch et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…OAS in humans and the dumbo phenotype in mice are both recessive phenotypes that result from loss-of-function mutations in the Hmx1 coding region (Schorderet et al, 2008;Munroe et al, 2009;Vaclavik et al, 2011;Gillespie et al, 2015). However, in rats, the recessive dumbo allele consists of a 5777 bp deletion ∼80 kb downstream of Hmx1.…”

Section: Introductionmentioning

confidence: 99%

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A distal 594bp ECR specifies Hmx1 expression in pinna and lateral facial morphogenesis and is regulated by Hox-Pbx-Meis

Rosin

Cox

et al. 2016

Development

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Hmx1 encodes a homeodomain transcription factor expressed in the developing lateral craniofacial mesenchyme, retina and sensory ganglia. Mutation or mis-regulation of Hmx1 underlies malformations of the eye and external ear in multiple species. Deletion or insertional duplication of an evolutionarily conserved region (ECR) downstream of Hmx1 has recently been described in rat and cow, respectively. Here, we demonstrate that the impact of Hmx1 loss is greater than previously appreciated, with a variety of lateral cranioskeletal defects, auriculofacial nerve deficits, and duplication of the caudal region of the external ear. Using a transgenic approach, we demonstrate that a 594 bp sequence encompassing the ECR recapitulates specific aspects of the endogenous Hmx1 lateral facial expression pattern. Moreover, we show that Hoxa2, Meis and Pbx proteins act cooperatively on the ECR, via a core 32 bp sequence, to regulate Hmx1 expression. These studies highlight the conserved role for Hmx1 in BA2-derived tissues and provide an entry point for improved understanding of the causes of the frequent lateral facial birth defects in humans.

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Section: Hmx1 Mutant Mice Exhibit Craniofacial and Cranioskeletal Anosupporting

confidence: 64%

Section: Hmx1 Mutant Mice Exhibit Craniofacial and Cranioskeletal Anomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A distal 594bp ECR specifies Hmx1 expression in pinna and lateral facial morphogenesis and is regulated by Hox-Pbx-Meis

Rosin

Cox

et al. 2016

Development

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Histochemical and Ultrastructural Study of Developing Gonial Bone With Reference to Initial Ossification of the Malleus and Reduction of Meckel's Cartilage in Mice

Shibata

Takahashi

Fujikawa

2019

The Anatomical Record

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Development of mouse gonial bone and initial ossification process of malleus were investigated. Before the formation of the gonial bone, the osteogenic area expressing alkaline phosphatase and Runx2 mRNA was widely recognized inferior to Meckel's cartilage. The gonial bone was first formed within the perichondrium at E16.0 via intramembranous ossification, surrounded the lower part of Meckel's cartilage, and then continued to extend anteriorly and medially until postnatal day (P) 3.0. At P0, multinucleated chondroclasts started to resorb the mineralized cartilage matrix with ruffled borders at the initial ossification site of the malleus (most posterior part of Meckel's cartilage). Almost all CD31-positive capillaries did not run through the gonial bone but entered the cartilage through the site where the gonial bone was not attached, indicating the forms of the initial ossification site of the malleus are similar to those at the secondary ossification center rather than the primary ossification center in the long bone. Then, the reducing process of the posterior part of Meckel's cartilage with extending gonial bone was investigated. Numerous tartrate-resistant acid phosphatase-positive mononuclear cells invaded the reducing Meckel's cartilage, and the continuity between the malleus and Meckel's cartilage was completely lost by P3.5. Both the cartilage matrix and the perichondrium were degraded, and they seemed to be incorporated into the periosteum of the gonial bone. The tensor tympani and tensor veli palatini muscles were attached to the ligament extending from the gonial bone. These findings indicated that the gonial bone has multiple functions and plays important roles in cranial formation.

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An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure

Harris

Juriloff

2010

Birth Defects Research

296

325

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The number of mouse mutants and strains with neural tube defects (NTDs) now exceeds 240, including 205 representing specific genes, 30 for unidentified genes, and 9 multifactorial strains. These mutants identify genes needed for embryonic neural tube closure. Reports of 50 new NTD mutants since our 2007 review (Harris and Juriloff, 2007) were considered in relation to the previously reviewed mutants to obtain new insights into mechanisms of NTD etiology. In addition to null mutations, some are hypomorphs or conditional mutants. Some mutations do not cause NTDs on their own, but do so in digenic, trigenic, and oligogenic combinations, an etiology that likely parallels the nature of genetic etiology of human NTDs. Mutants that have only exencephaly are fourfold more frequent than those that have spina bifida aperta with or without exencephaly. Many diverse cellular functions and biochemical pathways are involved; the NTD mutants draw new attention to chromatin modification (epigenetics), the protease-activated receptor cascade, and the ciliopathies. Few mutants directly involve folate metabolism. Prevention of NTDs by maternal folate supplementation has been tested in 13 mutants and reduces NTD frequency in six diverse mutants. Inositol reduces spina bifida aperta frequency in the curly tail mutant, and three new mutants involve inositol metabolism. The many NTD mutants are the foundation for a future complete genetic understanding of the processes of neural fold elevation and fusion along mechanistically distinct cranial-caudal segments of the neural tube, and they point to several candidate processes for study in human NTD etiology. Birth Defects Research (Part A) 88:653-669,

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Mouse H6 Homeobox 1 (Hmx1) mutations cause cranial abnormalities and reduced body mass

Cited by 54 publications

References 22 publications

A distal 594bp ECR specifies Hmx1 expression in pinna and lateral facial morphogenesis and is regulated by Hox-Pbx-Meis

A distal 594bp ECR specifies Hmx1 expression in pinna and lateral facial morphogenesis and is regulated by Hox-Pbx-Meis

Histochemical and Ultrastructural Study of Developing Gonial Bone With Reference to Initial Ossification of the Malleus and Reduction of Meckel's Cartilage in Mice

An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure

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