Itpr1 regulates the formation of anterior eye segment tissues derived from neural crest cells

Mutations in ITPR1 cause ataxia and aniridia in individuals with Gillespie syndrome (GLSP). However, the pathogenic mechanisms underlying aniridia remain unclear. We identified a de novo GLSP mutation hotspot in the 3′-region of ITPR1 in five individuals with GLSP. Furthermore, RNA-sequencing and immunoblotting revealed an eye-specific transcript of Itpr1 (218-aa isoform), encoding 218 amino acids (aa). This isoform is localized not only in the endoplasmic reticulum, but also in the nuclear and cytoplasmic membranes. Ocular-specific transcription was repressed by SOX9 and induced by c-MAF in the anterior eye segment (AES) tissues. Mice lacking seven base pairs of the last Itpr1 exon exhibited ataxia and aniridia, in which the iris lymphatic vessels, sphincter and dilator muscles, corneal endothelium and stroma were disrupted, but the neural crest cells persisted after the completion of AES formation. Our analyses revealed that the 218-aa isoform regulated the directionality of actin fibers and the intensity of focal adhesion. The isoform might control the nuclear entry of transcriptional regulators, such as YAP. It is possible that ITPR1 regulates both AES differentiation and muscle contraction in the iris.

Download Full-text

The hominoid-specific gene DSCR4 is involved in regulation of human leukocyte migration

10.1101/176503 ◽

2017 ◽

Author(s):

Morteza Mahmoudi Saber ◽

Marziyeh Karimiavargani ◽

Nilmini Hettiarachchi ◽

Michiaki Hamada ◽

Takanori Uzawa ◽

...

Keyword(s):

Down Syndrome ◽

Immune System ◽

Neural Crest ◽

De Novo ◽

Human Leukocyte ◽

Neural Crest Cells ◽

Human Cells ◽

Specific Gene ◽

Facial Morphology ◽

Specific Expression

AbstractDSCR4 (Down syndrome critical region 4) is an orphan retrotransposon-derived de-novo originated protein coding gene present only in hominoids (humans and great apes). Despite being located on the medically critical genomic region and abundance of evidences indicating its functionality, the role of this gene in human cells was utterly unknown. Due to absence of any prior knowledge regarding the function of DSCR4, for the first time here we used a gene-overexpression approach to discover biological importance and cellular roles of this gene. Our analysis strongly indicates DSCR4 to be mainly involved in regulation of the interconnected biological pathways related to cell migration, coagulation and immune system. We also showed that the predicted biological functions are consistent with tissue-specific expression of DSCR4 in migratory immune system leukocyte cells and neural crest cells that shape facial morphology of human embryo. Immune system and neural crest cells are also shown to be affected in Down syndrome patients who suffer from the same type of DSCR4 misregulation as in our study which further support our findings. Providing evidence for the critical roles of DSCR4 in human cells, our findings establish the basis for further investigations on the roles of DSCR4 in etiology of Down syndrome and unique characteristics of hominoids.

Download Full-text

Cis-acting regulatory sequences governing Wnt-1 expression in the developing mouse CNS

Development ◽

10.1242/dev.120.8.2213 ◽

1994 ◽

Vol 120 (8) ◽

pp. 2213-2224 ◽

Cited By ~ 17

Author(s):

Y. Echelard ◽

G. Vassileva ◽

A.P. McMahon

Keyword(s):

Neural Crest ◽

De Novo ◽

Ectopic Expression ◽

Neural Crest Cells ◽

Neural Tube Closure ◽

Regulatory Sequences ◽

Lacz Gene ◽

Mouse Development ◽

Enhancer Element ◽

Cis Acting

The protooncogene Wnt-1 encodes a short-range signal which is first expressed in, and appears to demarcate, the presumptive midbrain. Absence of Wnt-1 expression leads to the loss of this region of the brain. By the end of neural tube closure, expression of Wnt-1 extends down much of the dorsal midline of the central nervous system (CNS). Expression is exclusively limited to the CNS at this and later stages. We have investigated the regulation of Wnt-1 during mouse development. Analysis of the embryonic expression of Wnt-1-lacZ reporter constructs spanning nearly 30 kb of the Wnt-1 locus identified a 5.5 kb cis-acting 3′ enhancer element which confers correct temporal and spatial expression on the lacZ gene. Interestingly embryos express Wnt-1-lacZ transgenes in migrating neural crest cells which are derived from the dorsal CNS. Ectopic expression of the Wnt-1-lacZ transgenes may result from perdurance of beta-galactosidase activity in migrating neural crest cells originating from a Wnt-1-expressing region of the dorsal CNS. Alternatively, ectopic expression may arise from transient de novo activation of the transgenes in this cell population. These results are a first step towards addressing how regional cell signaling is established in the mammalian CNS. In addition, transgene expression provides a new tool for the analysis of neural crest development in normal and mutant mouse embryos.

Download Full-text