Hazel L. Sive
We probe molecular mechanisms underlying vertebrate development. One focus is the Extreme Anterior Domain, a facial signaling center that also forms the mouth. We examine the brain ventricular system and ‘basal constriction’, a novel cell shape change in the brain. A major focus is on neurodevelopmental disorders, including autism spectrum disorders, intellectual disability and epilepsy, in order to define novel therapeutics.Whitehead Member Hazel Sive studies development of the vertebrate embryo. Her group has made unique contributions to understanding how the face forms and how the brain develops its normal structure. Research in the Sive lab emphasizes craniofacial and brain disorders, using the accessible frog and zebrafish models.
Sive is a pioneer in analysis of the extreme anterior domain (EAD), a unique and important embryonic region she named. She used a simple organ, the mucus-secreting cement gland of frogs, as a marker for the extreme anterior and to define the genetic network by which an organ is positioned. The EAD also gives rise to the mouth and the Sive group has defined key steps necessary for mouth formation. Using their ‘facial transplant’ technique, her group made the unprecedented discovery that the EAD is also a facial signaling center, which guides neural crest cells into the developing face, where they form the jaws and other structures. Since the EAD is present in humans, the work is directly relevant for understanding human craniofacial anomalies.
A major focus of Sive’s research has been on development of the nervous system patterning. Using novel techniques, her laboratory defined some of the earliest molecular markers of the nervous system and regulators of the nervous system in both Xenopus and the zebrafish Danio. This work answered the age-old question of when the embryo decides to make a nervous system, and showed that future brain cells are set aside when the embryo is just a ball of cells.
Function of these genes, including otx2 and zic1 (opl), was studied using hormone-inducible fusion proteins, a technique first used in embryos by Sive. She also developed the first zebrafish ‘explant’ culture method, and so identified cell interactions that initiate brain development. As well, Sive identified retinoic acid as a regulator of brain patterning, and demonstrated its activity on expression of hindbrain Hox genes. And she defined additional roles for fibroblast growth factors in precise patterning of the hindbrain.
As structure and function are closely allied, Sive also focuses on how three-dimensional structure of the brain is generated by the processes of morphogenesis. Sive first identified and named “basal constriction” as a cell-shape-change occurring during brain morphogenesis. In addition, she identified and named the process of “epithelial relaxation,” a cell-sheet-stretching process that occurs as brain ventricles form. Indeed, she pioneered use of zebrafish to study the brain ventricular system—cavities filled with cerebrospinal fluid (CSF) that form the body’s “third circulation.” Using a unique drainage assay, Sive identified Retinol Binding Protein in the CSF as essential for survival of brain cells.
Sive has a long-standing interest in neurodevelopmental disorders, including those relating to mental health. A great challenge is that these disorders often involve multiple genes, whose contributions to a disorder is frequently unclear. Sive pioneered zebrafish as a tool for probing gene function associated with autism spectrum disorders. Her group has identified genes that interact and contribute to brain dysfunction in the prevalent and serious 16p11.2 deletion syndrome, most recently implicating lipid metabolism in symptomatology.
Sive received her B.Sc. Hons. from the University of Witwatersrand, Johannesburg, South Africa and Ph.D. from Rockefeller University. She leads the Working Group on Neural Disorders for the Zebrafish Disease Models Society. Sive also focuses on education and training, teaching Introductory Biology to undergraduates and Developmental Biology to graduate students. She is former Associate Dean of Science with oversight for diversity and education. Sive is Chair of the Committee on Student Life, Chair of the Faculty Postdoc Advisory Committee and co-Chair of the MITx Faculty Advisory Committee. She is Founding Director of the MIT-South Africa Program and Founding Coordinator of MIT-AFRICA. Dr. Sive is particularly interested in higher education, and the evolving role of faculty in teaching, and scaling of curriculum reform. Dr. Sive was selected as a 2015 MacVicar Fellow, MIT’s highest undergraduate teaching award.