Abnormal sympathetic nervous system development and physiological dysautonomia in Egr3-deficient mice

Eldredge, Laurie C.; Gao, Xin; Quach, David H.; Li, Lin; Han, Xiaoqiang; Lomasney, Jon W.; Tourtellotte, Warren G.

doi:10.1242/dev.023960

Cited by 43 publications

(57 citation statements)

References 50 publications

(71 reference statements)

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“…Thus, for these genes, expression changes found in aging arguably represent the continuation of a developmental trend. Our results, from both humans and macaques, suggest that a number of regulators, including the TF early growth response protein 3 (EGR3) involved in sympathetic neuron development (Eldredge et al 2008), and miR34a, involved in the apoptosis (Yamakuchi et al 2008) and tumor suppression in neuroblastoma (Cole et al 2008), might be responsible for at least some of these continuous expression changes (Fig. 6E).…”

Section: Aging As Extended Developmentmentioning

confidence: 85%

MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain

Somel

Guo²,

Fu³

et al. 2010

Genome Res.

285

345

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Changes in gene expression levels determine differentiation of tissues involved in development and are associated with functional decline in aging. Although development is tightly regulated, the transition between development and aging, as well as regulation of post-developmental changes, are not well understood. Here, we measured messenger RNA (mRNA), microRNA (miRNA), and protein expression in the prefrontal cortex of humans and rhesus macaques over the species' life spans. We find that few gene expression changes are unique to aging. Instead, the vast majority of miRNA and gene expression changes that occur in aging represent reversals or extensions of developmental patterns. Surprisingly, many gene expression changes previously attributed to aging, such as down-regulation of neural genes, initiate in early childhood. Our results indicate that miRNA and transcription factors regulate not only developmental but also post-developmental expression changes, with a number of regulatory processes continuing throughout the entire life span. Differential evolutionary conservation of the corresponding genomic regions implies that these regulatory processes, although beneficial in development, might be detrimental in aging. These results suggest a direct link between developmental regulation and expression changes taking place in aging.

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Section: Aging As Extended Developmentmentioning

confidence: 85%

MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain

Somel

Guo²,

Fu³

et al. 2010

Genome Res.

285

345

View full text Add to dashboard Cite

show abstract

“…In some experiments, tissues were isolated fresh for RNA and/or protein extraction. lacZ histochemistry was performed as previously described (Eldredge et al, 2008).…”

Section: Tissue Preparationmentioning

confidence: 99%

“…Primary neuron survival was performed as previously described and detailed as previously described (Eldredge et al, 2008).…”

Section: Immunohistochemistry and Western Blottingmentioning

confidence: 99%

A neuron autonomous role for the familial dysautonomia geneELP1in sympathetic and sensory target tissue innervation

Jackson¹,

Gruner

Qin

et al. 2014

Development

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Familial dysautonomia (FD) is characterized by severe and progressive sympathetic and sensory neuron loss caused by a highly conserved germline point mutation of the human ELP1/IKBKAP gene. Elp1 is a subunit of the hetero-hexameric transcriptional elongator complex, but how it functions in disease-vulnerable neurons is unknown. Conditional knockout mice were generated to characterize the role of Elp1 in migration, differentiation and survival of migratory neural crest (NC) progenitors that give rise to sympathetic and sensory neurons. Loss of Elp1 in NC progenitors did not impair their migration, proliferation or survival, but there was a significant impact on post-migratory sensory and sympathetic neuron survival and target tissue innervation. Ablation of Elp1 in post-migratory sympathetic neurons caused highly abnormal target tissue innervation that was correlated with abnormal neurite outgrowth/branching and abnormal cellular distribution of soluble tyrosinated α-tubulin in Elp1-deficient primary sympathetic and sensory neurons. These results indicate that neuron loss and physiologic impairment in FD is not a consequence of abnormal neuron progenitor migration, differentiation or survival. Rather, loss of Elp1 leads to neuron death as a consequence of failed target tissue innervation associated with impairments in cytoskeletal regulation.

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“…Embryos were dissected at E18.5, and organs were removed, fixed, and stained as previously described (42). Individual seminiferous tubule staining was completed by incubation of testes in PBS with 0.1% collagenase at 37 C for 1 h with rocking.…”

Section: Lacz Enzyme Histochemistrymentioning

confidence: 99%

Male Hypogonadism and Germ Cell Loss Caused by a Mutation in Polo-Like Kinase 4

2011

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The genetic etiologies of male infertility remain largely unknown. To identify genes potentially involved in spermatogenesis and male infertility, we performed genome-wide mutagenesis in mice with N-ethyl-N-nitrosourea and identified a line with dominant hypogonadism and patchy germ cell loss. Genomic mapping and DNA sequence analysis identified a novel heterozygous missense mutation in the kinase domain of Polo-like kinase 4 (Plk4), altering an isoleucine to asparagine at residue 242 (I242N). Genetic complementation studies using a gene trap line with disruption in the Plk4 locus confirmed that the putative Plk4 missense mutation was causative. Plk4 is known to be involved in centriole formation and cell cycle progression. However, a specific role in mammalian spermatogenesis has not been examined. PLK4 was highly expressed in the testes both pre- and postnatally. In the adult, PLK4 expression was first detected in stage VIII pachytene spermatocytes and was present through step 16 elongated spermatids. Because the homozygous Plk4(I242N/I242N) mutation was embryonic lethal, all analyses were performed using the heterozygous Plk4(+/I242N) mice. Testis size was reduced by 17%, and histology revealed discrete regions of germ cell loss, leaving only Sertoli cells in these defective tubules. Testis cord formation (embryonic day 13.5) was normal. Testis histology was also normal at postnatal day (P)1, but germ cell loss was detected at P10 and subsequent ages. We conclude that the I242N heterozygous mutation in PLK4 is causative for patchy germ cell loss beginning at P10, suggesting a role for PLK4 during the initiation of spermatogenesis.

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Abnormal sympathetic nervous system development and physiological dysautonomia in Egr3-deficient mice

Cited by 43 publications

References 50 publications

MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain

MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain

A neuron autonomous role for the familial dysautonomia geneELP1in sympathetic and sensory target tissue innervation

Male Hypogonadism and Germ Cell Loss Caused by a Mutation in Polo-Like Kinase 4

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