Our research focuses on the molecular mechanisms underlying vertebrate development, with additional emphasis on disorders that arise during development. One area of interest is face formation and the ‘Extreme Anterior Domain’ that forms the mouth and is also a facial signaling center. Much of our research addresses brain development, including the brain ventricular system that contains cerebrospinal fluid to form a ‘third circulation’, and ‘basal constriction’ a novel cell shape change we identified in the brain. A major focus is to define mechanisms underlying neurodevelopmental disorders including autism, schizophrenia and intellectual disability, and to screen for novel therapeutics. Our research uses the accessible frog and zebrafish models.
The Extreme Anterior Domain
Classical embryologists had noted an anterior region where ectoderm and endoderm are directly juxtaposed, without intervening mesoderm that is present in all deuterostomes. We named this region the ‘Extreme Anterior Domain’ (EAD) and showed it gives rise to the mouth. We are identifying steps and signaling pathways involved in mouth formation, previously demonstrating that canonical Wnt signaling inhibitors are required for normal basement membrane dynamics and mouth opening. Subsequently, we showed that the EAD is also a facial signaling center, which guides neural crest into the developing face, using the Kinin-Kallikrein pathway. The notion that the EAD is a signaling center was unanticipated, and this activity is likely to be conserved in mammals. Our work is relevant for understanding and treating human craniofacial defects.
Development and function of the brain ventricular system
Although it is clear that a neural tube is essential for vertebrate nervous system formation, there is poor understanding of why the tube is important. The lumen of the neural tube is filled with cerebrospinal fluid (CSF), of complex composition that forms ‘the third circulation’ in the brain and spinal cord. My group pioneered the zebrafish as a useful and accessible model for study of brain ventricle development and function. We identified mutants and genes that impact zebrafish brain ventricle formation, among these the Na+K+-ATPase that is essential for both neuroepithelial formation and CSF production. We developed a drainage assay that showed necessity for CSF in brain cell survival. Using mass spectrometry and complementation assays, we identified Retinol Binding Protein 4 (RBP4) as acting from the CSF through retinoic acid signaling to promote neuroepithelial cell survival. Ongoing analyses implicate abnormal CSF composition in neurodegenerative disorders.
Basal constriction during brain morphogenesis
The vertebrate brain develops from a tube, which becomes bent at stereotypical positions, to pack the brain into the protective skull. The first major bend to form separates the midbrain and hindbrain forming the midbrain-hindbrain boundary constriction (MHBC). Morphogenesis of the MHBC requires basal constriction, a novel cellular mechanism we described. Our data shows that an intact basement membrane is required, as well as Wnt-PCP signaling.
Meeting challenges in neurodevelopmental and psychiatric disorders
Understanding the causes of neurodevelopmental disorders is one of the greatest clinical challenges in brain health. Complex behavioral phenotypes and multigenic contributions make a broad range of approaches essential for defining molecular phenotypes and new treatments. We established the zebrafish as a useful system for analysis of autism spectrum and other psychiatric disorders. Our group has focused on the schizophrenia risk gene DISC1 and on the 16p11.2 CNV that is tightly associated with autism spectrum disorders, schizophrenia, intellectual disability and other phenotypes, and Pitt-Hopkins Syndrome a rare monogenic disorder. The 16p11.2 region contains 25 genes, and genetic data indicate that two or more genes synergize in symptomatology. Our recent studies have defined multiple synergistic dosage sensor genes, which begin to construct an “interaction map” in this important genomic region. The work makes a unique contribution to the neurodevelopmental research field.
Jacox, L.*, Sindelka, R.*, Chen, J., Rothman, A., Dickinson, A. and Sive, H. The extreme anterior domain is an essential craniofacial organizer acting through Kinin-Kallikrein signaling. Cell Rep. 8, 596-609, 2014. *equal contribution.
Chang, J.T., Lehtinen, M.K. and Sive, H. Zebrafish cerebrospinal fluid mediates cell survival through a retinoid signaling pathway. Dev. Neurobiol., 2015 May 15. doi: 10.1002/dneu.22300.
Blaker-Lee, A.,* Gupta, S.,* McCammon, J.,* De Rienzo, G. and Sive, H. Zebrafish homologs of 16p11.2, a genomic region associated with brain disorders, are active during brain development, and include two deletion dosage sensor genes. *equal contribution. Dis. Model. Mech. 5, 834-851, 2012. PMC3484866.
McCammon JM, Sive H. Challenges in understanding psychiatric disorders and developing therapeutics: a role for zebrafish. Dis Model Mech. 2015 Jul 1;8(7):647-56. doi: 10.1242/dmm.019620.