19 Feb 2020

Study strengthens link between cleft palate and ancient gene

Dr Marina Carpinelli (first author) and
Professor Stephen Jane (last author)
by Anne Crawford

Cleft lip and palate are common birth defects, affecting about one in 800 Australian babies. The conditions, which result in the baby’s facial parts failing to fuse during early foetal life, can affect the child’s social development, feeding, hearing and speech, as well as their appearance.

Now, Monash University scientists have found that Grhl2, part of an ancient gene family called Grainyhead-like (Grhl), plays a critical role in preventing cleft palate in combination with a gene called Zeb1.

The study was led by the Central Clinical School researchers in the Epidermal Development group - headed by Professor Stephen Jane - and by long-term collaborator Dr Sebastian Dworkin (now at La Trobe University). It was published late last month in Disease Models & Mechanisms.

First author Dr Marina Carpinelli said another group had found that Grhl3 caused cleft palate in humans with mutations; her group wanted to find out why.

“We were using knockout mice, trying to uncover the mechanism whereby Grhl2 controls the closure of the face,” she said. “We found that there’s another gene called Zeb1 that was upregulated in Grhl2-null embryos. We knocked out both genes in the same mouse.”

Perhaps surprisingly, the double knockout resulted in the closure of the face and secondary palate.

“Grhl2 and Zeb1, both transcription factors, have opposing effects on the cellular phenotype – Grhl2 tells cells to be epithelial, Zeb1 tells them to have a mesenchymal phenotype,” Dr Carpinelli said.

“Usually, if you remove two genes you don’t expect to return things back to normal,” she said. “In this case it led to a partial rescue focussed on the closure of the secondary palate,” she said.

However, some regions towards the front of the mouth, areas in the ‘primary palate’ were still cleft.

“We found that the balance between Grhl2 and Zeb1 is essential for normal closure, and we also found a delicate balance between epithelial and mesenchymal phenotypes.

“These pathways may be perturbed through mutation or through environmental factors in some patients with cleft palate,” she said.

While the study was preclinical it yielded important knowledge on which other researchers could build to find ways to prevent such birth defects, Dr Carpinelli said.

It is part of a larger body of work by the lab into developmental processes regulated by the highly conserved Grainyhead-like family of transcription factors, so-called because mutations in the grainyhead gene of drosophila give the fly an abnormal and ‘grainy’ head skeleton.

The Epidermal Development group is now pursuing work on Grhl3 and its role in spina bifida.
Grhl1-3 genes play key roles in a number of tissue fusion processes including epidermal wound healing, eyelid fusion and neurulation, the embryological process that forms the precursors of the central nervous system.

Professor Jane, who is Foundation Dean, Sub-Faculty of Translational Medicine and Public Health at Monash University, has been investigating developmental processes regulated by the Grainyhead-like family for more than 15 years. “This work represents another link with human disease, and importantly defines the mechanism by which palate fusion failure can occur,” said Professor Jane.

Dr Carpinelli, who is passionate about teaching and genetics, and fascinated by embryonic development, is a Senior Research Officer in the Jane research group.

She is keen to hear from any students interested in embryonic development and birth defects. You can contact Dr Carpinelli on marina.carpinelli@monash.edu.

Carpinelli MR, de Vries ME, Auden A, Butt T, Deng Z, Partridge DD, Miles LB, Georgy SR, Haigh JJ, Darido C, Brabletz S, Brabletz T, Stemmler MP, Dworkin S, Jane SM. Inactivation of Zeb1 in GRHL2-deficient mouse embryos rescues mid-gestation viability and secondary palate closure. Dis Model Mech. 2020 Jan 31. pii: dmm.042218. doi: 10.1242/dmm.042218. [Epub ahead of print]


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