Hmx2 homeobox gene control of murine vestibular morphogenesis

Development ◽  
2001 ◽  
Vol 128 (24) ◽  
pp. 5017-5029 ◽  
Author(s):  
Weidong Wang ◽  
Edwin K. Chan ◽  
Shira Baron ◽  
Thomas Van De Water ◽  
Thomas Lufkin
Keyword(s):  
Inner Ear ◽  
Cell Fate ◽  
Critical Role ◽  
Homeobox Gene ◽  
Significant Loss ◽  
Targeted Disruption ◽  
Surface Ectoderm ◽  
Dorsal Portion ◽  
Temporal And Spatial ◽  
Semicircular Ducts

Development of the vertebrate inner ear is characterized by a series of genetically programmed events involving induction of surface ectoderm, preliminary morphogenesis, specification and commitment of sensory, nonsensory and neuronal cells, as well as outgrowth and restructuring of the otocyst to form a complex labyrinth. Hmx2, a member of the Hmx homeobox gene family, is coexpressed with Hmx3 in the dorsolateral otic epithelium. Targeted disruption of Hmx2 in mice demonstrates the temporal and spatial involvement of Hmx2 in the embryonic transition of the dorsal portion (pars superior) of the otocyst to a fully developed vestibular system. In Hmx2 null embryos, a perturbation in cell fate determination in the lateral aspect of the otic epithelium results in reduced cell proliferation in epithelial cells, which includes the vestibular sensory patches and semicircular duct fusion plates, as well as in the adjacent mesenchyme. Consequently, enlargement and morphogenesis of the pars superior of the otocyst to form a complex labyrinth of cavities and ducts is blocked, as indicated by the lack of any distinguishable semicircular ducts, persistence of the primordial vestibular diverticula, significant loss in the three cristae and the macula utriculus, and a fused utriculosaccular chamber. The developmental regulators Bmp4, Dlx5 and Pax2 all play a critical role in inner ear ontogeny, and the expression of each of these genes is affected in the Hmx2 null otocyst suggesting a complex regulatory role for Hmx2 in this genetic cascade. Both Hmx2 and Hmx3 transcripts are coexpressed in the developing central nervous system including the neural tube and hypothalamus. A lack of defects in the CNS, coupled with the fact that not all of the Hmx2-positive regions in developing inner ear are impaired in the Hmx2 null mice, suggest that Hmx2 and Hmx3 have both unique and overlapping functions during embryogenesis.

scholarly journals Transcriptome-Wide Analysis Reveals a Role for Extracellular Matrix and Integrin Receptor Genes in Otic Neurosensory Differentiation from Human iPSCs

2021 ◽  
Vol 22 (19) ◽  
pp. 10849
Author(s):  
Lejo Johnson Chacko ◽  
Hanae Lahlou ◽  
Claudia Steinacher ◽  
Said Assou ◽  
Yassine Messat ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Inner Ear ◽  
Cell Fate ◽  
Time Course ◽  
Critical Role ◽  
Pcr Analysis ◽  
Sensory Cells ◽  
Gene Markers ◽  
Human Ipscs

We analyzed transcriptomic data from otic sensory cells differentiated from human induced pluripotent stem cells (hiPSCs) by a previously described method to gain new insights into the early human otic neurosensory lineage. We identified genes and biological networks not previously described to occur in the human otic sensory developmental cell lineage. These analyses identified and ranked genes known to be part of the otic sensory lineage program (SIX1, EYA1, GATA3, etc.), in addition to a number of novel genes encoding extracellular matrix (ECM) (COL3A1, COL5A2, DCN, etc.) and integrin (ITG) receptors (ITGAV, ITGA4, ITGA) for ECM molecules. The results were confirmed by quantitative PCR analysis of a comprehensive panel of genes differentially expressed during the time course of hiPSC differentiation in vitro. Immunocytochemistry validated results for select otic and ECM/ITG gene markers in the in vivo human fetal inner ear. Our screen shows ECM and ITG gene expression changes coincident with hiPSC differentiation towards human otic neurosensory cells. Our findings suggest a critical role of ECM-ITG interactions with otic neurosensory lineage genes in early neurosensory development and cell fate determination in the human fetal inner ear.

The role of the msh homeobox gene during Drosophila neurogenesis: implication for the dorsoventral specification of the neuroectoderm

Development ◽  
1997 ◽  
Vol 124 (16) ◽  
pp. 3099-3109 ◽  
Author(s):  
T. Isshiki ◽  
M. Takeichi ◽  
A. Nose
Keyword(s):  
Cell Fate ◽  
Neural Development ◽  
Ectopic Expression ◽  
Homeobox Gene ◽  
Loss Of Function ◽  
Spinal Cord Development ◽  
Dorsal Portion ◽  
Msx Genes

Development of the Drosophila central nervous system begins with the delamination of neural and glial precursors, called neuroblasts, from the neuroectoderm. An early and important step in the generation of neural diversity is the specification of individual neuroblasts according to their position. In this study, we describe the genetic analysis of the msh gene which is likely to play a role in this process. The msh/Msx genes are one of the most highly conserved families of homeobox genes. During vertebrate spinal cord development, Msx genes (Msx1-3) are regionally expressed in the dorsal portion of the developing neuroectoderm. Similarly in Drosophila, msh is expressed in two longitudinal bands that correspond to the dorsal half of the neuroectoderm, and subsequently in many dorsal neuroblasts and their progeny. We showed that Drosophila msh loss-of-function mutations led to cell fate alterations of neuroblasts formed in the dorsal aspect of the neuroectoderm, including a possible dorsal-to-ventral fate switch. Conversely, ectopic expression of msh in the entire neuroectoderm severely disrupted the proper development of the midline and ventral neuroblasts. The results provide the first in vivo evidence for the role of the msh/Msx genes in neural development, and support the notion that they may perform phylogenetically conserved functions in the dorsoventral patterning of the neuroectoderm.

Inner ear and maternal reproductive defects in mice lacking the Hmx3 homeobox gene

Development ◽  
1998 ◽  
Vol 125 (4) ◽  
pp. 621-634 ◽  
Author(s):  
W. Wang ◽  
T. Van De Water ◽  
T. Lufkin
Keyword(s):  
Inner Ear ◽  
Homeobox Gene ◽  
Preimplantation Embryos ◽  
Sensory Cells ◽  
Wild Type ◽  
Targeted Disruption ◽  
Horizontal Semicircular Canal ◽  
Hierarchical Relationship ◽  
Inner Ear Development ◽  
Post Implantation

The Hmx homeobox gene family is of ancient origin, being present in species as diverse as Drosophila, sea urchin and mammals. The three members of the murine Hmx family, designated Hmx1, Hmx2 and Hmx3, are expressed in tissues that suggest a common functional role in sensory organ development and pregnancy. Hmx3 is one of the earliest markers for vestibular inner ear development during embryogenesis, and is also upregulated in the myometrium of the uterus during pregnancy. Targeted disruption of the Hmx3 gene results in mice with abnormal circling behavior and severe vestibular defects owing to a depletion of sensory cells in the saccule and utricle, and a complete loss of the horizontal semicircular canal crista, as well as a fusion of the utricle and saccule endolymphatic spaces into a common utriculosaccular cavity. Both the sensory and secretory epithelium of the cochlear duct appear normal in the Hmx3 null animals. The majority of Hmx3 null females have a reproductive defect. Hmx3 null females can be fertilized and their embryos undergo normal preimplantation development, but the embryos fail to implant successfully in the Hmx3 null uterus and subsequently die. Transfer of preimplantation embryos from mutant Hmx3 uterine horns to wild-type pseudopregnant females results in successful pregnancy, indicating a failure of the Hmx3 null uterus to support normal post-implantation pregnancy. Molecular analysis revealed the perturbation of Hmx, Wnt and LIF gene expression in the Hmx3 null uterus. Interestingly, expression of both Hmx1 and Hmx2 is downregulated in the Hmx3 null uterus, suggesting a hierarchical relationship among the three Hmx genes during pregnancy.

scholarly journals Mechanosensation and Mechanotransduction by Lymphatic Endothelial Cells Act as Important Regulators of Lymphatic Development and Function

2021 ◽  
Vol 22 (8) ◽  
pp. 3955
Author(s):  
László Bálint ◽  
Zoltán Jakus
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Mechanical Forces ◽  
Lymphatic Endothelial Cells ◽  
Lymphatic Development ◽  
And Function ◽  
The Impact

Our understanding of the function and development of the lymphatic system is expanding rapidly due to the identification of specific molecular markers and the availability of novel genetic approaches. In connection, it has been demonstrated that mechanical forces contribute to the endothelial cell fate commitment and play a critical role in influencing lymphatic endothelial cell shape and alignment by promoting sprouting, development, maturation of the lymphatic network, and coordinating lymphatic valve morphogenesis and the stabilization of lymphatic valves. However, the mechanosignaling and mechanotransduction pathways involved in these processes are poorly understood. Here, we provide an overview of the impact of mechanical forces on lymphatics and summarize the current understanding of the molecular mechanisms involved in the mechanosensation and mechanotransduction by lymphatic endothelial cells. We also discuss how these mechanosensitive pathways affect endothelial cell fate and regulate lymphatic development and function. A better understanding of these mechanisms may provide a deeper insight into the pathophysiology of various diseases associated with impaired lymphatic function, such as lymphedema and may eventually lead to the discovery of novel therapeutic targets for these conditions.

A GATA family transcription factor is expressed along the embryonic dorsoventral axis in Drosophila melanogaster

Development ◽  
1993 ◽  
Vol 119 (4) ◽  
pp. 1055-1065 ◽  
Author(s):  
J. Winick ◽  
T. Abel ◽  
M.W. Leonard ◽  
A.M. Michelson ◽  
I. Chardon-Loriaux ◽  
...  
Keyword(s):  
Dna Binding ◽  
Cell Fate ◽  
Zinc Finger ◽  
Sequence Similarity ◽  
Vertebrate Development ◽  
Drosophila Development ◽  
Gata Factors ◽  
Factors Analysis ◽  
Dorsal Portion ◽  
Dorsal Cell Fate

The GATA transcription factors are a family of C4 zinc finger-motif DNA-binding proteins that play defined roles in hematopoiesis as well as presumptive roles in other tissues where they are expressed (e.g., testis, neuronal and placental trophoblast cells) during vertebrate development. To investigate the possibility that GATA proteins may also be involved in Drosophila development, we have isolated and characterized a gene (dGATAa) encoding a factor that is quite similar to mammalian GATA factors. The dGATAa protein sequence contains the two zinc finger DNA-binding domain of the GATA class but bears no additional sequence similarity to any of the vertebrate GATA factors. Analysis of dGATAa gene transcription during Drosophila development revealed that its mRNA is expressed at high levels during early embryogenesis, with transcripts first appearing in the dorsal portion of the embryo just after cellularization. As development progresses, dGATAa mRNA is present at high levels in the dorsal epidermis, suggesting that dGATAa may be involved in determining dorsal cell fate. The pattern of expression in a variety of dorsoventral polarity mutants indicates that dGATAa lies downstream of the zygotic patterning genes decapentaplegic and zerknullt.

Hes1 is a negative regulator of inner ear hair cell differentiation

Development ◽  
2000 ◽  
Vol 127 (21) ◽  
pp. 4551-4560 ◽  
Author(s):  
J.L. Zheng ◽  
J. Shou ◽  
F. Guillemot ◽  
R. Kageyama ◽  
W.Q. Gao
Keyword(s):  
Cell Differentiation ◽  
Hair Cell ◽  
Inner Ear ◽  
Cell Fate ◽  
Hair Cells ◽  
Outer Hair Cells ◽  
Negative Regulator ◽  
Pcr Analysis ◽  
Loss Of Function ◽  
Hair Cell Differentiation

Hair cell fate determination in the inner ear has been shown to be controlled by specific genes. Recent loss-of-function and gain-of-function experiments have demonstrated that Math1, a mouse homolog of the Drosophila gene atonal, is essential for the production of hair cells. To identify genes that may interact with Math1 and inhibit hair cell differentiation, we have focused on Hes1, a mammalian hairy and enhancer of split homolog, which is a negative regulator of neurogenesis. We report here that targeted deletion of Hes1 leads to formation of supernumerary hair cells in the cochlea and utricle of the inner ear. RT-PCR analysis shows that Hes1 is expressed in inner ear during hair cell differentiation and its expression is maintained in adulthood. In situ hybridization with late embryonic inner ear tissue reveals that Hes1 is expressed in supporting cells, but not hair cells, of the vestibular sensory epithelium. In the cochlea, Hes1 is selectively expressed in the greater epithelial ridge and lesser epithelial ridge regions which are adjacent to inner and outer hair cells. Co-transfection experiments in postnatal rat explant cultures show that overexpression of Hes1 prevents hair cell differentiation induced by Math1. Therefore Hes1 can negatively regulate hair cell differentiation by antagonizing Math1. These results suggest that a balance between Math1 and negative regulators such as Hes1 is crucial for the production of an appropriate number of inner ear hair cells.

scholarly journals Inhibition of Vascular Nitric Oxide after Rat Chronic Brain Hypoperfusion: Spatial Memory and Immunocytochemical Changes

2005 ◽  
Vol 25 (6) ◽  
pp. 663-672 ◽  
Author(s):  
Jack C. de la Torre ◽  
Gjumrakch Aliev
Keyword(s):  
Nitric Oxide ◽  
Spatial Memory ◽  
Memory Function ◽  
Critical Role ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Significant Loss ◽  
Electron Microscopic ◽  
Vessel Occlusion ◽  
Common Carotid Artery Occlusion

An aging rat model of chronic brain hypoperfusion (CBH) that mimics human mild cognitive impairment (MCI) was used to examine the role of nitric oxide synthase (NOS) isoforms on spatial memory function. Rats with CBH underwent bilateral common carotid artery occlusion (2-vessel occlusion (2-VO)) for either 26 or 8 weeks and were compared with nonoccluded sham controls (S-VO). The neuronal and endothelial (nNOS/eNOS) constitutive inhibitor nitro-L-arginine methyl ester (L-NAME) 20 mg/kg was administered after 26 weeks for 3 days to 2-VO and S-VO groups and spatial memory was assessed with a modified Morris watermaze test. Only 2-VO rats worsened their spatial memory ability after L-NAME. Electron microscopic immunocytochemical examination using an antibody against eNOS showed 2-VO rats had significant loss or absence of eNOS-containing positive gold particles in hippocampal endothelium and these changes were associated with endothelial cell compression, mitochondrial damage and heavy amyloid deposition in hippocampal capillaries and perivascular region. In the 8-week study, three groups of 2-VO rats were administered an acute dose of 7-NI, aminoguanidine or L-NIO, the relatively selective inhibitors of nNOS, inducible NOS and eNOS. Only rats administered the eNOS inhibitor L-NIO worsened markedly their watermaze performance ( P=0.009) when compared with S-VO nonoccluded controls. We conclude from these findings that vascular nitric oxide derived from eNOS may play a critical role in spatial memory function during CBH possibly by keeping cerebral perfusion optimal through its regulation of microvessel tone and cerebral blood flow and that disruption of this mechanism can result in spatial memory impairment. These findings may identify therapeutic targets for preventing MCI and treating Alzheimer's disease.

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