The Hand2 Gene Dosage Effect in Developmental Defects and Human Congenital Disorders

Tamura, Masahito; Amano, Takanori; Shiroishi, Toshihiko

doi:10.1016/b978-0-12-405943-6.00003-8

Cited by 15 publications

(10 citation statements)

References 89 publications

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“…Through combinational analysis of multiple mouse models and single cell characterization, we conclude that HAND2 expression alteration is the primary molecular effect of inhibition of Hand2os1 in heterogeneous cell populations. HAND2 expression undergoes a decrease after E10.5 and then remains low throughout the remaining course of heart development (Srivastava et al, 1997;Tamura et al, 2014). The observed upregulation of HAND2 in E11.5 and E16.5 Hand2os1 F/F embryos may also reflect improper downregulation of HAND2 during cardiac development.…”

Section: Discussionmentioning

confidence: 95%

“…HAND2, a transcription factor that promotes ventricular cardiomyocyte expansion and cardiac reprogramming, is a crucial regulator of embryonic heart development (McFadden et al, 2005;Song et al, 2012;Srivastava et al, 1997). Cardiac expression of HAND2 is initially detected in the cardiac crescent at E7.75, continues throughout the linear heart tube at E8.5, is specifically enhanced in the developing right ventricle (RV) and outflow tract (OFT) until E9.5-E10.0, and is downregulated in the cardiac mesoderm but maintained in the neural crest-derived aortic arch arteries (Srivastava et al, 1997;Tamura et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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The lncRNA Hand2os1/Uph locus orchestrates heart development through regulation of precise expression of Hand2

et al. 2019

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Exploration and dissection of potential actions and effects of long noncoding RNA (lncRNA) in animals remain challenging. Here, using multiple knockout mouse models and single cell RNA sequencing, we demonstrate that the divergent lncRNA Hand2os1/Uph has a key complex modulatory effect on the expression of its neighboring gene HAND2 and subsequently on heart development and function. Short deletion of the Hand2os1 promoter in mouse diminishes Hand2os1 transcription to ∼8-32%, but fails to affect HAND2 expression and yields no discernable heart phenotypes. Interestingly, full-length deletion of Hand2os1 in mouse causes moderate yet prevalent upregulation of HAND2 in hundreds of cardiac cells, leading to profound biological consequences, including dysregulated cardiac gene programs, congenital heart defects and perinatal lethality. We propose that the Hand2os1 locus dampens HAND2 expression to restrain cardiomyocyte proliferation, thereby orchestrating a balanced development of cardiac cell lineages. This study highlights the regulatory complexity of the lncRNA Hand2os1 on HAND2 expression, emphasizing the need for complementary genetic and single cell approaches to delineate the function and primary molecular effects of an lncRNA in animals.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

The lncRNA Hand2os1/Uph locus orchestrates heart development through regulation of precise expression of Hand2

et al. 2019

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“…It also has been demonstrated that EDN1 is also necessary for Hand2 expression in the pharyngeal arch (Sasaki, Nichols, & Kimmel, ; Tamura, Amano, & Shiroishi, ). Hand2 is expressed in the first pharyngeal arch and not only plays a role in the dorsoventral/proximodistal pattern of the mandibular arch, but also initiates tongue morphogenesis (Barron et al, ; Parada & Chai, ; Tamura et al, ; Yanagisawa, Clouthier, Richardson, Charite, & Olson, ). In humans, the HAND2 gene resides at chromosome 4q.…”

Section: Genetic Perspectivementioning

confidence: 99%

The ontogeny of Robin sequence

Logjes

Breugem

Haaften

et al. 2018

American J of Med Genetics Pt A

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The triad of micrognathia, glossoptosis, and concomitant airway obstruction defined as "Robin sequence" (RS) is caused by oropharyngeal developmental events constrained by a reduced stomadeal space. This sequence of abnormal embryonic development also results in an anatomical configuration that might predispose the fetus to a cleft palate. RS is heterogeneous and many different etiologies have been described including syndromic, RS-plus, and isolated forms. For an optimal diagnosis, subsequent treatment and prognosis, a thorough understanding of the embryology and pathogenesis is necessary. This manuscript provides an update about our current understanding of the development of the mandible, tongue, and palate and possible mechanisms involved in the development of RS. Additionally, we provide the reader with an up-to-date summary of the different etiologies of this phenotype and link this to the embryologic, developmental, and genetic mechanisms.

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“…Hence, as long as transcriptional activity is present in the Handsdown region, Hand2 can be negatively regulated and its expression level adjusted. The dosage of Hand2 is particularly important as loss of one copy of the Hand2 gene, as well as the gain of an additional copy of the Hand2 gene, causes malformations during development ( Tamura et al, 2014 ). In addition to these lncRNA loci flanking the Hand2 gene, additional putative enhancers are predicted up- and downstream of Hand2 , underlining the complex regulome of this important gene in development.…”

Section: Lncrna Genes In the Genomementioning

confidence: 99%

Beyond the RNA-dependent function of LncRNA genes

Ali

Grote

2020

eLife

206

116

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While long non-coding RNA (lncRNA) genes have attracted a lot of attention in the last decade, the focus regarding their mechanisms of action has been primarily on the RNA product of these genes. Recent work on several lncRNAs genes demonstrates that not only is the produced RNA species important, but also that transcription of the lncRNA locus alone can have regulatory functions. Like the functions of lncRNA transcripts, the mechanisms that underlie these genome-based functions are varied. Here we highlight some of these examples and provide an outlook on how the functional mechanisms of a lncRNA gene can be determined.

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The Hand2 Gene Dosage Effect in Developmental Defects and Human Congenital Disorders

Cited by 15 publications

References 89 publications

The lncRNA Hand2os1/Uph locus orchestrates heart development through regulation of precise expression of Hand2

The lncRNA Hand2os1/Uph locus orchestrates heart development through regulation of precise expression of Hand2

The ontogeny of Robin sequence

Beyond the RNA-dependent function of LncRNA genes

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