Selected Publications:

The zebrafish as a psychiatric and neurodevelopmental tool

Understanding the causes of psychiatric and neurodevelopmental disorders is one of the greatest clinical challenges. 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 an useful system for analysis of autism spectrum and other psychiatric disorders. Part of this was developing the notion of an animal ‘tool’ that can address disease, even without recapitulating all human symptoms. This nomenclature has been useful for many investigators. My group has focused on the schizophrenia risk gene DISC1 and on the 16p11.2 CNV that is tightly associated with autism spectrum disorders, schizophrenia and other phenotypes. We demonstrated that DISC1 regulates the Wnt-PCP pathway. We initiated studies on 16p11.2 deletion syndrome, and have made significant strides in connecting genes with symptoms. We demonstrated that zebrafish 16p11.2 homologs, kif22 and aldoa, are dosage sensors, and have defined the first genetic interactome, identifying pairwise functional connection amongst these genes. Using genetic mutants we identified fam57b as a key ‘hub’ gene among the 16p11.2 cohort, that interacts with a presynaptic exocytosis regulator, encoded by doc2a. The work makes a unique contribution to the psychiatric research field, and studies are ongoing. I served as P.I. on all aspects of these studies.

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  • DeRienzo, G., Bishop, J. A., Mao, Y., Pan, L., Ma, T.P., Moens, C.B., Tsai, L.H. and Sive, H. Disc1 regulates both -catenin-mediated and non-canonical Wnt signaling during vertebrate embryogenesis. FASEB J. 25, 4184-4197, 2011. PMCID: PMC3236629.
  • 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 first authors. Dis. Model. Mech. 5, 834-851, 2012. PMCID: PMC3484866.
  • McCammon, J.M. and Sive, H. Challenges in understanding psychiatric disorders and developing therapeutics: A role for zebrafish. Dis. Model Mech. 8(7), 647-656, 2015. PMCID: PMC4486859.
  • McCammon, J.M., Blaker-Lee, A., Chen, X. and Sive. H. The 16p11.2 homologs fam57ba and doc2a generate certain bran and body phenotypes, Hum. Mol. Genet. 26(19), 3699-3712, 2017.

The brain ventricular system

Formation of how the vertebrate neural tube formed, as precursor to the central nervous system was widely studied. However, few were asking why the tube formed. Since it takes the embryo huge effort to make a neural tube, we set about asking why is there a neural tube? My group pioneered the zebrafish as a useful and accessible model for study of brain ventricle development and function. We developed techniques to label, drain and refill the ventricles. We identified multiple mutants that impact zebrafish brain ventricle formation. Among the corresponding genes is the NaK-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, and is part of the answer to the question ‘why is there a neural tube?’. Using mass spectrometry and CSF complementation assays, we identified Retinol Binding Protein 4 (RBP4) as acting from the CSF through retinoic acid signaling to promote neuroepithelial cell survival. I served as P.I. on all aspects of these studies.

  • Lowery, L.A. and Sive, H. Initial formation of zebrafish brain ventricles occurs independently of circulation and requires the nagie oko and snakehead/atp1a1a.1 gene products. Development, 132, 2057-2067, 2005.
  • Chang, J.T., Lowery. L.A., and Sive, H. Multiple roles for the Na,K-ATPase subunits, Atp1a1 and Fxyd1, during brain ventricle development. Dev. Biol. 368(2), 312-322, 2012. PMCID: PMC3402628.
  • Chang, J.T., Lehtinen, M.K. and Sive, H. Zebrafish cerebrospinal fluid mediates cell survival through a retinoid signaling pathway. Dev. Neurobiol., 76(1),75-92, 2016. Epub 2015 June 8. PMCID: PMC4644717.
  • Fame, R.M., Chang, J.T., Hong, A., Aponte-Santiago, N.A. and Sive, H. Directional cerebrospinal fluid movement between brain ventricles in larval zebrafish. Fluids Barriers CNS 13(1), 11, 2016. PMCID: PMC4915066

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. However the significance of this region was unknown. I named the anterior, mesoderm-free region the ‘Extreme Anterior Domain’ (EAD). I decided to use the Xenopus cement gland as a positional marker for this region, and my group identified the molecular signals that position this organ. We went on to define the mouth as an EAD derivative, and the processes/genes involved in mouth formation. Subsequently, we identified the EAD as a facial organizer, which guides neural crest into the developing face. We built this field. Our work established the cement gland as a useful positional marker. We re-opened classical investigations into mouth formation and defined novel molecular mechanisms, as well as a novel facial transplant technique. The notion that the EAD is an organizer was unanticipated, and this activity is likely to be conserved in mammals. I served as P.I. on all aspects of these studies.

  • Dickinson, A. and Sive, H. The Wnt antagonists, Frzb-1 and Crescent locally regulate basement membrane dissolution in the developing primary mouth. Development 136, 1071-81, 2009. PMCID: PMC2685928.
  • 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. PMCID: PMC4135435. * equal contribution.
  • Jacox, L., Chen, J., Rothman, A., Lathrop-Marshall, H. and Sive, H. Formation of a ‘pre-mouth array’ from the extreme anterior domain is directed by neural crest and Wnt/PCP signaling. Cell Rep. 16(5):1445-55, 2016. PMCID: PMC4972695.
  • Chen, J., Jacox. L.A., Saldanha, F. and Sive, H. Mouth Development. WIREs Dev Biol, 6:n/a, e275. doi: 10.1002/wdev.275, 2017. PMCID: PMC5574021