期刊
DEVELOPMENTAL BIOLOGY
卷 319, 期 2, 页码 179-191出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ydbio.2008.03.036
关键词
Hand2(dHand); neural crest; bHLH; neurogenesis; cell type-specific gene regulation; sympathetic ganglia; TH; Gata3 Phox2
资金
- NHLBI NIH HHS [P01 HL085098, R01 HL061677, P01 HL085098-01A10001, R01 HL061677-09] Funding Source: Medline
- NIA NIH HHS [P30 AG013319, 1P30-AG13319] Funding Source: Medline
- NIDCR NIH HHS [DE14181, K02 DE014765, DE14765, R01 DE014181] Funding Source: Medline
- NIDDK NIH HHS [R01 DK067064-03, R01 DK067064, R01 DK067285] Funding Source: Medline
- NINDS NIH HHS [R01 NS040644, R01 NS040644-07S1, NS040644, R01 NS040644-07] Funding Source: Medline
- Telethon [TGM06S01, TGM06A04] Funding Source: Medline
- Wellcome Trust [075555] Funding Source: Medline
Neural crest-derived structures that depend critically upon expression of the basic helix-loop-helix DNA binding protein Hand2 for normal development include craniofacial cartilage and bone, the outflow tract of the heart, cardiac cushion, and noradrenergic sympathetic ganglion neurons. Loss of Hand2 is embryonic lethal by E9.5, obviating a genetic analysis of its in-vivo function. We have overcome this difficulty by specific deletion of Hand2 in neural crest-derived cells by crossing our line of floxed Hand2 mice with Wnt1-Cre transgenic mice. Our analysis of Hand2 knock-out in neural crest-derived cells reveals effects on development in all neural crest-derived structures where Hand2 is expressed. in the autonomic nervous system, conditional disruption of Hand2 results in a significant and progressive loss of neurons as well as a significant loss of TH expression. Hand2 affects generation of the neural precursor pool of cells by affecting both the proliferative capacity of the progenitors as well as affecting expression of Phox2a and Gata3, DNA binding proteins important for the cell autonomous development of noradrenergic neurons. Our data suggest that Hand2 is a multifunctional DNA binding protein affecting differentiation and cell type-specific gene expression in neural crest-derived noradrenergic sympathetic ganglion neurons. Hand2 has a pivotal function in a non-linear cross-regulatory network of DNA binding proteins that affect cell autonomous control of differentiation and cell type-specific gene expression. (c) 2008 Elsevier Inc. All rights reserved.
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