The Carboxyl-Terminus of TRANSPARENT TESTA GLABRA1 Is Critical for Its Functions in Arabidopsis

The Arabidopsis WD40 repeat protein TRANSPARENT TESTA GLABRA1 (TTG1) regulates cell fate determination, including trichome initiation and root hair formation, as well as secondary metabolism such as flavonoid biosynthesis and seed coat mucilage production. TTG1 regulates different processes via regulating the expression of its downstream target genes by forming MYB-bHLH-WD40 (MBW) activator complexes with different R2R3 MYB and bHLH transcription factors. Here, we report the identification of the carboxyl (C)-terminus as a critical domain for TTG1′s functions in Arabidopsis. We found that the ttg1Δ15aa mutant shows pleiotropic phenotypes identical to a TTG1 loss-of-function mutant. Gene sequencing indicates that a single nucleotide substitution in TTG1 led to a premature stop at the W327 residue, leading to the production of a truncated TTG1 protein with a deletion of the last 15 C-terminal amino acids. The expression of TTG1 under the control of its native promoter fully restored the ttg1Δ15aa mutant phenotypes. Consistent with these observations, the expression levels of TTG1 downstream genes such as GLABRA2 (GL2) and CAPRICE (CPC) were reduced in the ttg1Δ15aa mutant. Assays in Arabidopsis protoplast show that TTG1Δ15aa failed to interact with the bHLH transcription factor GL3, and the deletion of the last 3 C-terminal amino acids or the 339L amino acid alone fully abolished the interaction of TTG1 with GL3. Furthermore, the expression of TTG1Δ3aa under the control of TTG1 native promoter failed to restore the ttg1Δ15aa mutant phenotypes. Taken together, our results suggest that the C-terminal domain of TTG1 is required for its proper function in Arabidopsis.

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TRANSPARENT TESTA GLABRA1, a Key Regulator in Plants with Multiple Roles and Multiple Function Mechanisms

International Journal of Molecular Sciences ◽

10.3390/ijms21144881 ◽

2020 ◽

Vol 21 (14) ◽

pp. 4881 ◽

Cited By ~ 2

Author(s):

Hainan Tian ◽

Shucai Wang

Keyword(s):

Transcription Factor ◽

Cell Fate ◽

Target Genes ◽

Multiple Roles ◽

26S Proteasome ◽

Bhlh Transcription Factor ◽

Transcription Activator ◽

Downstream Target ◽

Transparent Testa ◽

Functional Mechanisms

TRANSPARENT TESTA GLABRA1 (TTG1) is a WD40 repeat protein. The phenotypes caused by loss-of-function of TTG1 were observed about half a century ago, but the TTG1 gene was identified only about twenty years ago. Since then, TTG1 has been found to be a plant-specific regulator with multiple roles and multiple functional mechanisms. TTG1 is involved in the regulation of cell fate determination, secondary metabolisms, accumulation of seed storage reserves, plant responses to biotic and abiotic stresses, and flowering time in plants. In some processes, TTG1 may directly or indirectly regulate the expression of downstream target genes via forming transcription activator complexes with R2R3 MYB and bHLH transcription factors. Whereas in other processes, TTG1 may function alone or interact with other proteins to regulate downstream target genes. On the other hand, the studies on the regulation of TTG1 are very limited. So far, only the B3-domain family transcription factor FUSCA3 (FUS3) has been found to regulate the expression of TTG1, phosphorylation of TTG1 affects its interaction with bHLH transcription factor TT2, and TTG1 proteins can be targeted for degradation by the 26S proteasome. Here, we provide an overview of TTG1, including the identification of TTG1, the functions of TTG1, the possible function mechanisms of TTG1, and the regulation of TTG1. We also proposed potential research directions that may shed new light on the regulation and functional mechanisms of TTG1 in plants.

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Key Mechanisms of Early Lung Development

Pediatric and Developmental Pathology ◽

10.2350/07-06-0290.1 ◽

2007 ◽

Vol 10 (5) ◽

pp. 335-347 ◽

Cited By ~ 54

Author(s):

Jun Kimura ◽

Gail H. Deutsch

Keyword(s):

Respiratory Tract ◽

Cell Fate ◽

Target Genes ◽

Critical Role ◽

Hierarchical Classification ◽

Branching Morphogenesis ◽

Loss Of Function ◽

Innovative Strategies ◽

Downstream Target ◽

Molecular Events

Lung morphogenesis requires the integration of multiple regulatory factors, which results in a functional air-blood interface required for gas exchange at birth. The respiratory tract is composed of endodermally derived epithelium surrounded by cells of mesodermal origin. Inductive signaling between these 2 tissue compartments plays a critical role in formation and differentiation of the lung, which is mediated by evolutionarily conserved signaling families used reiteratively during lung formation, including the fibroblast growth factor, hedgehog, retinoic acid, bone morphogenetic protein, and Wnt signaling pathways. Cells coordinate their response to these signaling proteins largely through transcription factors, which determine respiratory cell fate and pattern formation via the activation and repression of downstream target genes. Gain- and loss-of-function studies in null mutant and transgenic mice models have greatly facilitated the identification and hierarchical classification of these molecular programs. In this review, we highlight select molecular events that drive key phases of pulmonary development, including specification of a lung cell fate, primary lung bud formation, tracheoesophageal septation, branching morphogenesis, and proximal-distal epithelial patterning. Understanding the genetic pathways that regulate respiratory tract development is essential to provide insight into the pathogenesis of congenital anomalies and to develop innovative strategies to treat inherited and acquired lung disease.

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Mechanisms in Endocrinology: Notch signaling in skeletal health and disease

Acta Endocrinologica ◽

10.1530/eje-13-0115 ◽

2013 ◽

Vol 168 (6) ◽

pp. R95-R103 ◽

Cited By ~ 42

Author(s):

Stefano Zanotti ◽

Ernesto Canalis

Keyword(s):

Notch Signaling ◽

Cell Fate ◽

Target Genes ◽

Skeletal Development ◽

Alagille Syndrome ◽

Notch Signaling Pathway ◽

Loss Of Function ◽

Skeletal Health ◽

Notch Ligand ◽

Ligand Interactions

Notch receptors are single-pass transmembrane proteins that determine cell fate. Upon Notch ligand interactions, proteolytic cleavages release the Notch intracellular domain, which translocates to the nucleus to regulate the transcription of target genes, including Hairy enhancer of split (Hes) and Hes related to YRPW motif (Hey). Notch is critical for skeletal development and activity of skeletal cells, and dysregulation of Notch signaling is associated with human diseases affecting the skeleton. Inherited or sporadic mutations in components of the Notch signaling pathway are associated with spondylocostal dysostosis, spondylothoracic dysostosis and recessive brachydactyly, diseases characterized by skeletal patterning defects. Inactivating mutations of the Notch ligandJAG1or ofNOTCH2are associated with Alagille syndrome, and activating mutations inNOTCH2are associated with Hajdu–Cheney syndrome (HCS). Individuals affected by HCS exhibit osteolysis in distal phalanges and osteoporosis. NOTCH is activated in selected tumors, such as osteosarcoma, and in breast cancer cells that form osteolytic bone metastases. In conclusion, Notch regulates skeletal development and bone remodeling, and gain- or loss-of-function mutations of Notch signaling result in important skeletal diseases.

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osr1 couples intermediate mesoderm cell fate with temporal dynamics of vessel progenitor cell differentiation

Development ◽

10.1242/dev.198408 ◽

2021 ◽

Author(s):

Elliot A. Perens ◽

Jessyka T. Diaz ◽

Agathe Quesnel ◽

Amjad Askary ◽

J. Gage Crump ◽

...

Keyword(s):

Transcription Factor ◽

Cell Fate ◽

Regulatory Networks ◽

Temporal Dynamics ◽

Bhlh Transcription Factor ◽

Transcriptional Regulatory Networks ◽

Mesoderm Cell ◽

Intermediate Mesoderm ◽

Transcriptional Regulatory ◽

Mutant Phenotypes

Transcriptional regulatory networks refine gene expression boundaries to define the dimensions of organ progenitor territories. Kidney progenitors originate within the intermediate mesoderm (IM), but the pathways that establish the boundary between the IM and neighboring vessel progenitors are poorly understood. Here, we delineate roles for the zinc finger transcription factor Osr1 in kidney and vessel progenitor development. Zebrafish osr1 mutants display decreased IM formation and premature emergence of lateral vessel progenitors (LVPs). These phenotypes contrast with the increased IM and absent LVPs observed with loss of the bHLH transcription factor Hand2, and loss of hand2 partially suppresses osr1 mutant phenotypes. hand2 and osr1 are expressed together in the posterior mesoderm, but osr1 expression decreases dramatically prior to LVP emergence. Overexpressing osr1 during this timeframe inhibits LVP development while enhancing IM formation and can rescue the osr1 mutant phenotype. Together, our data demonstrate that osr1 modulates the extent of IM formation and the temporal dynamics of LVP development, suggesting that a balance between levels of osr1 and hand2 expression is essential to demarcate the kidney and vessel progenitor territories.

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NeuroD regulates multiple functions in the developing neural retina in rodent

Development ◽

10.1242/dev.126.1.23 ◽

1999 ◽

Vol 126 (1) ◽

pp. 23-36 ◽

Cited By ~ 21

Author(s):

E.M. Morrow ◽

T. Furukawa ◽

J.E. Lee ◽

C.L. Cepko

Keyword(s):

Cell Fate ◽

Neural Retina ◽

Bhlh Transcription Factor ◽

Loss Of Function ◽

Fourfold Increase ◽

Helix Loop Helix ◽

Retinal Explants ◽

Fate Decision ◽

And Function

The expression and function of the basic helix-loop-helix (bHLH) transcription factor NeuroD were studied in the developing neural retina in rodent. neuroD was expressed in areas of undetermined retinal cells as well as developing photoreceptors and amacrine interneurons. Expression was maintained in a subset of mature photoreceptors in the adult retina. Using both loss-of-function and gain-of-function approaches, NeuroD was found to play multiple roles in retinal development. (1) NeuroD was found to be a critical regulator of the neuron versus glial cell fate decision. Retinal explants derived from NeuroD-null mice demonstrated a three- to fourfold increase in Muller glia. Forced expression of neuroD in progenitors in rat using retroviruses hastened cell cycle withdrawal and blocked gliogenesis in vivo. (2) NeuroD appeared to regulate interneuron development, favouring amacrine over bipolar differentiation. Forced NeuroD expression resulted in an increase in amacrine interneurons and a decrease in bipolar interneurons. In the complementary experiment, retinae derived from NeuroD-null mice demonstrated a twofold increase in bipolar interneurons and a delay in amacrine differentiation. (3) NeuroD appeared to be essential for the survival of a subset of rod photoreceptors. In conclusion, these results implicate NeuroD in a variety of developmental functions including cell fate determination, differentiation and neuron survival.

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osr1 couples intermediate mesoderm cell fate with temporal dynamics of vessel progenitor cell differentiation

10.1101/2020.11.14.383141 ◽

2020 ◽

Cited By ~ 1

Author(s):

Elliot A. Perens ◽

Jessyka T. Diaz ◽

Agathe Quesnel ◽

Amjad Askary ◽

J. Gage Crump ◽

...

Keyword(s):

Transcription Factor ◽

Cell Fate ◽

Regulatory Networks ◽

Temporal Dynamics ◽

Bhlh Transcription Factor ◽

Transcriptional Regulatory Networks ◽

Mesoderm Cell ◽

Intermediate Mesoderm ◽

Transcriptional Regulatory ◽

Mutant Phenotypes

ABSTRACTTranscriptional regulatory networks refine gene expression boundaries throughout embryonic development to define the precise dimensions of organ progenitor territories. Kidney progenitors originate within the intermediate mesoderm (IM), but the pathways that establish the boundary between the IM and its neighboring vessel progenitors are poorly understood. Here, we delineate new roles for the zinc finger transcription factor Osr1 in kidney and vessel progenitor development. Zebrafish osr1 mutants display decreased IM formation and premature emergence of neighboring lateral vessel progenitors (LVPs). These phenotypes contrast with the increased IM and absent LVPs observed with loss of the bHLH transcription factor Hand2, and loss of hand2 partially suppresses the osr1 mutant phenotypes. hand2 and osr1 are both expressed in the posterior lateral mesoderm, but osr1 expression decreases dramatically prior to LVP emergence. Overexpressing osr1 inhibits LVP development while enhancing IM formation. Together, our data demonstrate that osr1 modulates both the extent of IM formation and the temporal dynamics of LVP development, suggesting that a balance between levels of osr1 and hand2 expression is essential to demarcate the dimensions of kidney and vessel progenitor territories.SUMMARY STATEMENTAnalysis of the osr1 mutant phenotype reveals roles in determining the extent of intermediate mesoderm formation while inhibiting premature differentiation of neighboring vessel progenitors.

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Hairless is required for the development of adult sensory organ precursor cells in Drosophila

Development ◽

10.1242/dev.111.1.89 ◽

1991 ◽

Vol 111 (1) ◽

pp. 89-104 ◽

Cited By ~ 12

Author(s):

A.G. Bang ◽

V. Hartenstein ◽

J.W. Posakony

Keyword(s):

Cell Fate ◽

Spatial Arrangement ◽

Cell Types ◽

Precursor Cells ◽

Precursor Cell ◽

Sensory Organ ◽

Specific Cell ◽

Loss Of Function ◽

Sensory Organ Precursor ◽

Mutant Phenotypes

Reduction of the wild-type activity of the gene Hairless (H) results in two major phenotypic effects on the mechanosensory bristles of adult Drosophila. Bristles are either ‘lost’ (i.e. the shaft and socket fail to appear) or they exhibit a ‘double socket’ phenotype, in which the shaft is apparently transformed into a second socket. Analysis of the phenotypes conferred by a series of H mutant genotypes demonstrates (1) that different sensilla exhibit different patterns of response to decreasing levels of H+ function, and (2) that the ‘bristle loss’ phenotype results from greater loss of H+ function than the ‘double socket’ phenotype. The systematic study of H allelic combinations enabled us to identify genotypes that reliably produce specific mutant defects in particular positions on the bodies of adult flies. This permitted us to investigate the cellular development of sensilla in these same positions in larvae and pupae and thereby establish the developmental basis for the mutant phenotypes. We have found that H is required for at least two steps of adult sensillum development. In positions where ‘double socket’ microchaetes appear on the notum of H mutant flies, sensillum precursor cells are present in the developing pupa and divide normally, but their progeny adopt an aberrant spatial arrangement and fail to differentiate correctly. In regions of the notum exhibiting ‘bristle loss’ in adult H mutants, we were unable at the appropriate stages of development to detect sensillum-specific cell types, the precursor cell divisions that generate them, or the primary precursor cells themselves. Thus, the H ‘bristle loss’ phenotype appears to reflect a very early defect in sensillum development, namely the failure to specify and/or execute the sensory organ precursor cell fate. This finding indicates that H is one of a small number of identified genes for which the loss-of-function phenotype is the failure of sensillum precursor cell development.

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A Long Lost Key Opens an Ancient Lock: Drosophila Myb Causes a Synthetic Multivulval Phenotype in Nematodes

10.1101/788265 ◽

2019 ◽

Author(s):

Paul J. Vorster ◽

Paul Goetsch ◽

Tilini U. Wijeratne ◽

Keelan Z. Guiley ◽

Laura Andrejka ◽

...

Keyword(s):

Cell Fate ◽

Cell Cycle Progression ◽

Target Genes ◽

Suppressor Gene ◽

Last Common Ancestor ◽

Loss Of Function ◽

Core Complex ◽

C Elegans

ABSTRACTThe five-protein MuvB core complex (LIN9/Mip130, LIN37/Mip40, LIN52, LIN54/Mip120, and LIN53/p55CAF1/RBBP4) has been highly conserved during the evolution of animals. This nuclear complex interacts with proteins encoded by the RB tumor suppressor gene family and its associated E2F-DP transcription factors to form DREAM complexes that repress the expression of genes that regulate cell cycle progression and cell fate. The MuvB core complex also interacts with proteins encoded by the Myb oncogene family to form the Myb-MuvB complexes that activate many of the same target genes. We show that animal-type Myb genes and proteins are present in Bilateria, Cnidaria, and Placozoa, the latter including some of the simplest known animal species. However, bilaterian nematode worms appear to have lost their animal-type Myb genes hundreds of millions of years ago. Nevertheless, the amino acids in the LIN9 and LIN52 proteins that directly interact with the MuvB-binding domains of human B-Myb and Drosophila Myb are conserved in C. elegans. Here we show that, despite greater than 500 million years since their last common ancestor, the Drosophila melanogaster Myb protein can bind to the nematode LIN9 and LIN52 family proteins in vitro and can cause a synthetic multivulval (synMuv) phenotype in vivo. This phenotype is similar to that caused by loss-of-function mutations in C. elegans synMuvB class genes including those that encode homologs of the MuvB core, RB, E2F, and DP. Furthermore, amino acid substitutions in the MuvB-binding domain of Drosophila Myb that disrupt its functions in vitro and in vivo also disrupt its activity in C. elegans. We speculate that nematodes and other animals may contain another protein that can bind to LIN9 and LIN52 in order to activate transcription of genes repressed by DREAM complexes.

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Identification of a novel homozygous loss-of-function mutation in FUCA1 gene causing severe fucosidosis: A case report

Journal of International Medical Research ◽

10.1177/03000605211005975 ◽

2021 ◽

Vol 49 (4) ◽

pp. 030006052110059

Author(s):

Xinwen Zhang ◽

Shaozhi Zhao ◽

Hongwei Liu ◽

Xiaoyan Wang ◽

Xiaolei Wang ◽

...

Keyword(s):

Amino Acids ◽

Lysosomal Storage Disorder ◽

Autosomal Recessive ◽

Signs And Symptoms ◽

Lysosomal Storage ◽

Loss Of Function ◽

Wild Type ◽

Single Nucleotide ◽

Whole Exome ◽

Exon 1

Fucosidosis is a rare lysosomal storage disorder characterized by deficiency of α-L-fucosidase with an autosomal recessive mode of inheritance. Here, we describe a 4-year-old Chinese boy with signs and symptoms of fucosidosis but his parents were phenotypically normal. Whole exome sequencing (WES) identified a novel homozygous single nucleotide deletion (c.82delG) in the exon 1 of the FUCA1 gene. This mutation will lead to a frameshift which will result in the formation of a truncated FUCA1 protein (p.Val28Cysfs*105) of 132 amino acids approximately one-third the size of the wild type FUCA1 protein (466 amino acids). Both parents were carrying the mutation in a heterozygous state. This study expands the mutational spectrum of the FUCA1 gene associated with fucosidosis and emphasises the benefits of WES for accurate and timely clinical diagnosis of this rare disease.

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