Open Access Research article

The buccohypophyseal canal is an ancestral vertebrate trait maintained by modulation in sonic hedgehog signaling

Roman H Khonsari12*, Maisa Seppala13, Alan Pradel4, Hugo Dutel56, Gaël Clément5, Oleg Lebedev7, Sarah Ghafoor1, Michaela Rothova18, Abigael Tucker1, John G Maisey4, Chen-Ming Fan9, Maiko Kawasaki1, Atsushi Ohazama1, Paul Tafforeau10, Brunella Franco11, Jill Helms12, Courtney J Haycraft13, Albert David14, Philippe Janvier5, Martyn T Cobourne13 and Paul T Sharpe1

Author affiliations

1 Department of Craniofacial Development and Stem Cell Research, Comprehensive Biomedical Research Center, Dental Institute, King’s College London, London, UK

2 Service de Chirurgie Maxillo-Faciale, Centre Hospitalier Universitaire Hôtel-Dieu, Nantes, France

3 Department of Orthodontics, Dental Institute, King’s College London, Guy’s Hospital, London, UK

4 American Museum of Natural History, New York City, NY, USA

5 CNRS-UMR 7207, Muséum National d’Histoire Naturelle, Paris, France

6 CNRS-UMR 7179, Muséum National d’Histoire Naturelle, Paris, France

7 Paleontological Institute of Russian Academy of Science, Moscow, Russian Federation

8 Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic

9 Department of Embryology, Carnegie Institution of Washington, Baltimore, USA

10 European Synchrotron Radiation Facility, Grenoble, France

11 Department of Pediatrics, Università degli Studi di Napoli Federico II, Naples, Italy

12 Department of Surgery, Stanford University, Palo Alto, CA, USA

13 College of Dental Medicine, Craniofacial Biology, Medical University of South Carolina, Carolina, SC, USA

14 Service de Génétique Clinique, Centre Hospitalier Universitaire Hôtel-Dieu, Nantes, France

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Citation and License

BMC Biology 2013, 11:27  doi:10.1186/1741-7007-11-27

Published: 28 March 2013



The pituitary gland is formed by the juxtaposition of two tissues: neuroectoderm arising from the basal diencephalon, and oral epithelium, which invaginates towards the central nervous system from the roof of the mouth. The oral invagination that reaches the brain from the mouth is referred to as Rathke’s pouch, with the tip forming the adenohypophysis and the stalk disappearing after the earliest stages of development. In tetrapods, formation of the cranial base establishes a definitive barrier between the pituitary and oral cavity; however, numerous extinct and extant vertebrate species retain an open buccohypophyseal canal in adulthood, a vestige of the stalk of Rathke’s pouch. Little is currently known about the formation and function of this structure. Here we have investigated molecular mechanisms driving the formation of the buccohypophyseal canal and their evolutionary significance.


We show that Rathke’s pouch is located at a boundary region delineated by endoderm, neural crest-derived oral mesenchyme and the anterior limit of the notochord, using CD1, R26R-Sox17-Cre and R26R-Wnt1-Cre mouse lines. As revealed by synchrotron X-ray microtomography after iodine staining in mouse embryos, the pouch has a lobulated three-dimensional structure that embraces the descending diencephalon during pituitary formation. Polarisfl/fl; Wnt1-Cre, Ofd1-/- and Kif3a-/- primary cilia mouse mutants have abnormal sonic hedgehog (Shh) signaling and all present with malformations of the anterior pituitary gland and midline structures of the anterior cranial base. Changes in the expressions of Shh downstream genes are confirmed in Gas1-/- mice. From an evolutionary perspective, persistence of the buccohypophyseal canal is a basal character for all vertebrates and its maintenance in several groups is related to a specific morphology of the midline that can be related to modulation in Shh signaling.


These results provide insight into a poorly understood ancestral vertebrate structure. It appears that the opening of the buccohypophyseal canal depends upon Shh signaling and that modulation in this pathway most probably accounts for its persistence in phylogeny.

Buccohypophyseal canal; Chondrichthyans; Coelacanth; Endoderm; Knock-out mouse; Midline; Neural crest; Primary cilia; Shh