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Regulation of Head Size by the Extreme Anterior Domain: A Target for Microcephaly

52 Pages Posted: 15 Jan 2020 Sneak Peek Status: Review Complete

See all articles by Justin Chen

Justin Chen

Whitehead Institute for Biomedical Research; Massachusetts Institute of Technology (MIT)

Francesca Saldhana

Boston Childrens’ Hospital - Department of Plastic and Oral Surgery; Whitehead Institute for Biomedical Research

Hong Thi Tran

Center for Medical Genetics - Department for Biomedical Molecular Biology

Kris Vleminckx

Center for Medical Genetics - Department for Biomedical Molecular Biology

Hazel Sive

Whitehead Institute for Biomedical Research; Massachusetts Institute of Technology (MIT)

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Abstract

The characteristic size and shape of brain and face in each species suggests that these aspects of head development are coordinately controlled. We show that in Xenopus this control includes signaling activity of the conserved Extreme Anterior Domain (EAD). Extirpation of the EAD truncates facial cartilages derived from the first, second and third neural crest streams, and surprisingly, also reducing forebrain and midbrain size, indicating that the EAD extends long-range organizing function across multiple tissues of the developing head. Part of this function depends on the beta-catenin Wnt inhibitors Frzb and Crescent that are produced by the EAD, since their EAD-specific loss of function (LOF) is associated with reduction of facial cartilages and brain. These data, together with transgenic reporter analysis indicate that the EAD has a signaling range of approximately 40 cell diameters, with activity present by the end of neurulation. Targets of EAD signaling include pharyngeal arch regulatory gene expression, as well as cell proliferation in neural crest, forebrain and midbrain. Our findings identify a signaling mechanism that ensures coordinate development of multiple tissues contributing to the head. The study implies that disruption of EAD organizer activity may underlie disorders such as microcephaly, where anomalies are observed in both brain size and the facial skeleton.

Keywords: craniofacial development, brain, Neural crest, Head size, extreme anterior domain, Beta-catenin wnt, Sfrp, microcephaly, organizer

Suggested Citation

Chen, Justin and Saldhana, Francesca and Tran, Hong Thi and Vleminckx, Kris and Sive, Hazel, Regulation of Head Size by the Extreme Anterior Domain: A Target for Microcephaly. ISCIENCE-D-19-01458. Available at SSRN: https://ssrn.com/abstract=3519574 or http://dx.doi.org/10.2139/ssrn.3519574
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Justin Chen (Contact Author)

Whitehead Institute for Biomedical Research

455 Main Street
Cambridge, MA 02142
United States

Massachusetts Institute of Technology (MIT)

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Francesca Saldhana

Boston Childrens’ Hospital - Department of Plastic and Oral Surgery

United States

Whitehead Institute for Biomedical Research

455 Main Street
Cambridge, MA 02142
United States

Hong Thi Tran

Center for Medical Genetics - Department for Biomedical Molecular Biology

Belgium

Kris Vleminckx

Center for Medical Genetics - Department for Biomedical Molecular Biology

Belgium

Hazel Sive

Whitehead Institute for Biomedical Research

455 Main Street
Cambridge, MA 02142
United States

Massachusetts Institute of Technology (MIT)

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

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