New molecular insight into vertebrate brain development

Nov 17, 2008

In the December 1st issue of G&D, Dr. Fred H. Gage (The Salk Institute for Biological Studies) and colleagues reveal a role for the Hippo signaling pathway in the regulation of vertebrate neural development, identifying new factors – and potential therapeutic targets – that may be involved in congenital brain size disorders and neurological tumor formation.

Establishing the basic embryonic brain requires the formation of a hollow neural tube, which serves as the rudimentary central nervous system, as well as the controlled proliferation and differentiation of neural progenitor cells into various specialized cell types.

The Hippo pathway is an ancient conserved signaling cascade that is known to regulate organ size in the fly and mouse. Previous research has demonstrated that Hippo signaling serves as a brake on cell growth and proliferation by preventing another protein, YAP, from entering the nucleus and activating pro-growth genes.

Drs. Xinwei Cao, Samuel Pfaff and Fred Gage now report that Hippo signaling is a critical master regulator of bran size in vertebrates that functions by restricting instructing the survival, proliferation and differentiation of neural precursor cells. In addition, the researchers identified the TEA domain (TEAD) transcription factor protein as the long-sought-after cognate DNA-binding partner of YAP in the nucleus.

Using genetic manipulation of chick embryos, the scientists demonstrated the consequences of altered Hippo signaling on vertebrate neural tube development. Increased YAP/TEAD activity induced neural progenitor cell overproliferation and the formation of an expanded neural progenitor cell population. Decreased YAP/TEAD activity led to increased cell death, while repression of YAP/TEAD target genes induced premature neuronal differentiation.

Owing to the evolutionary conservation of the Hippo signaling pathway, Dr. Gage states that "understanding the HIPPO path may bring insights to human brain malformations. There are a number of brain size defects for which we are considering a follow up, including microcephaly and Autism, where the overall brain size is affected but structures retain the proportionality. The function of the HIPPO pathway also has implications for brain size evolution, which is of great interested to us."

Their paper will be made available online ahead of print on 11/17 at genesdev.org.

Source: Cold Spring Harbor Laboratory

Explore further: Schizophrenia's genetic 'skyline' rising: Suspect common variants soar from 30 to 108

add to favorites email to friend print save as pdf

Related Stories

Recommended for you

Mysterious esophagus disease is autoimmune after all

11 hours ago

(Medical Xpress)—Achalasia is a rare disease – it affects 1 in 100,000 people – characterized by a loss of nerve cells in the esophageal wall. While its cause remains unknown, a new study by a team of researchers at ...

Diagnostic criteria for Christianson Syndrome

Jul 21, 2014

Because the severe autism-like condition Christianson Syndrome was only first reported in 1999 and some symptoms take more than a decade to appear, families and doctors urgently need fundamental information ...

New technique maps life's effects on our DNA

Jul 20, 2014

Researchers at the BBSRC-funded Babraham Institute, in collaboration with the Wellcome Trust Sanger Institute Single Cell Genomics Centre, have developed a powerful new single-cell technique to help investigate how the environment ...

User comments : 0