Expression of Hand2 is sufficient for neurogenesis and cell type–specific gene expression in the enteric nervous system

Hendershot, Tyler J.; Liu, Hongbin; Sarkar, Anjali A.; Giovannucci, David R.; Clouthier, David E.; Abe, Makoto; Howard, Marthe J.

doi:10.1002/dvdy.20989

Cited by 77 publications

(99 citation statements)

References 52 publications

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“…were viable, healthy and fertile (Hendershot et al, 2007;Hendershot et al, 2008) and showed no alterations in skull morphology (data not shown). We next crossed Hand2 fl/fl mice with the Wnt1-Cre transgenic strain to target the Hand2 gene deletion to NCCs (Chai et al, 2000).…”

Section: Discussionmentioning

confidence: 90%

“…Conditional ablation of Hand2 in NCCs has revealed a crucial role for Hand2 in the development of sympathetic ganglion neurons (Hendershot et al, 2008;Morikawa et al, 2007), the enteric nervous system (Hendershot et al, 2007;D'Autreaux et al, 2007) and the cardiac outflow tract (Holler et al, 2010). In addition, conditional inactivation of Hand2 in the developing palatal epithelium has uncovered a role for Hand2 in palatal shelf fusion (Xiong et al, 2009).…”

Section: Ba/bamentioning

confidence: 99%

“…flox/flox (Hand2 fl/fl ) (Hendershot et al, 2007;Hendershot et al, 2008), Hand2 fl/- (Hendershot et al, 2008), Wnt1-Cre (Danielian et al, 1998) and R26R (Soriano, 1999) mice have been described previously. , Cre and lacZ genotyping were performed as described previously (Ruest and Clouthier, 2009;Soriano, 1999;Hendershot et al, 2008).…”

Section: Hand2mentioning

confidence: 99%

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Downregulation of Dlx5 and Dlx6 expression by Hand2 is essential for initiation of tongue morphogenesis

et al. 2011

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SUMMARYLower jaw development is a complex process in which multiple signaling cascades establish a proximal-distal organization. These cascades are regulated both spatially and temporally and are constantly refined through both induction of normal signals and inhibition of inappropriate signals. The connective tissue of the tongue arises from cranial neural crest cell-derived ectomesenchyme within the mandibular portion of the first pharyngeal arch and is likely to be impacted by this signaling. Although the developmental mechanisms behind later aspects of tongue development, including innervation and taste acquisition, have been elucidated, the early patterning signals driving ectomesenchyme into a tongue lineage are largely unknown. We show here that the basic helix-loop-helix transcription factor Hand2 plays key roles in establishing the proximaldistal patterning of the mouse lower jaw, in part through establishing a negative-feedback loop in which Hand2 represses Dlx5 and Dlx6 expression in the distal arch ectomesenchyme following Dlx5-and Dlx6-mediated induction of Hand2 expression in the same region. Failure to repress distal Dlx5 and Dlx6 expression results in upregulation of Runx2 expression in the mandibular arch and the subsequent formation of aberrant bone in the lower jaw along with proximal-distal duplications. In addition, there is an absence of lateral lingual swelling expansion, from which the tongue arises, resulting in aglossia. Hand2 thus appears to establish a distal mandibular arch domain that is conducive for lower jaw development, including the initiation of tongue mesenchyme morphogenesis.

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Section: Discussionmentioning

confidence: 90%

Section: Ba/bamentioning

confidence: 99%

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Downregulation of Dlx5 and Dlx6 expression by Hand2 is essential for initiation of tongue morphogenesis

et al. 2011

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“…The function of Hand genes in the autonomic nervous system is thus not limited to noradrenergic phenotypic expression. Because Hand2 expression in postnatal day (P)19 embryonic carcinoma cells causes the expression of peripheral neural markers, such as peripherin 1, and its expression occurs before neurons arise (Morikawa et al, 2005), crest-derived precursors may require Hand2 to become neurons rather than only for the specification of their neurotransmitter-defined identity (Hendershot et al, 2007;Howard, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Hand genes are expressed in developing mouse Hendershot et al, 2007;Hollenberg et al, 1995) and chick (Wu and Howard, 2002) gut. In situ hybridization has suggested that Hand2 is expressed in the presumptive enteric nervous system (ENS) in mice (Dai et al, 2004) and chicks (Wu and Howard, 2002).…”

Section: Introductionmentioning

confidence: 99%

Hand2is necessary for terminal differentiation of enteric neurons from crest-derived precursors but not for their migration into the gut or for formation of glia

et al. 2007

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Hand genes encode basic helix-loop-helix transcription factors that are expressed in the developing gut, where their function is unknown. We now report that enteric Hand2 expression is limited to crest-derived cells, whereas Hand1 expression is restricted to muscle and interstitial cells of Cajal. Hand2 is developmentally regulated and is intranuclear in precursors but cytoplasmic in neurons. Neurons develop in explants from wild-type but not Hand2 -/-bowel, although, in both, crest-derived cells are present and glia arise. Similarly, small interfering RNA (siRNA) silencing of Hand2 in enteric crest-derived cells prevents neuronal development. Terminally differentiated enteric neurons do not develop after conditional inactivation of Hand2 in migrating crest-derived cells; nevertheless, conditional Hand2 inactivation does not prevent precursors from expressing early neural markers. We suggest that enteric neuronal development occurs in stages and that Hand2 expression is required for terminal differentiation but not for precursors to enter the neuronal lineage.

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Hand factors as regulators of cardiac morphogenesis and implications for congenital heart defects

Vincentz

Barnes

Firulli

2011

Birth Defects Research

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Almost 15 years of careful study have established the related bHLH transcription factors Hand1 and Hand2 as critical for heart development across evolution. Hand factors make broad contributions, revealed through animal models, to the development of multiple cellular lineages that ultimately contribute to the heart. They perform critical roles in ventricular cardiomyocyte growth, differentiation, morphogenesis, and conduction. They are also important for the proper development of the cardiac outflow tract, epicardium, and endocardium. Molecularly, they function both through DNA-binding and through protein-protein interactions, which are regulated transcriptionally, post-transcriptionally by microRNAs, and post-translationally through phospho-regulation, Although direct Hand factor transcriptional targets are progressively being identified, confirmed direct targets of Hand factor transcriptional activity in the heart are limited. Identification of these targets will be critical to model the mechanisms by which Hand factor bHLH interactions affect developmental pathways. Improved understanding of Hand factor-mediated transcriptional cascades will be necessary to determine how Hand factor disregulation translates to human disease phenotypes. The following review summarizes the insight animal models have provided into the regulation and function of these factors during heart development, and the recent findings that suggest roles for HAND1 and HAND2 in human congenital heart disease.

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Expression of Hand2 is sufficient for neurogenesis and cell type–specific gene expression in the enteric nervous system

Cited by 77 publications

References 52 publications

Downregulation of Dlx5 and Dlx6 expression by Hand2 is essential for initiation of tongue morphogenesis

Downregulation of Dlx5 and Dlx6 expression by Hand2 is essential for initiation of tongue morphogenesis

Hand2is necessary for terminal differentiation of enteric neurons from crest-derived precursors but not for their migration into the gut or for formation of glia

Hand factors as regulators of cardiac morphogenesis and implications for congenital heart defects

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