Written by Henry Chang and Rebecca Varghese
Imagine all that needs to be done, biologically, for you to grow into a functional human being. Despite any self-perceived flaws, you are perfect—your organs function and your limbs are complete and where they should be. For that to have happened, genes had to have been turned on and off at the right place and time with the help of regulatory enzymes. The same is true for the brain, which dictates how we think, how we breathe, and basically how we experience life. Although great progress has been made in understanding learning and memory, much remains unknown about the brain and its functions.
At the Center for Complex Biological Systems (CCBS) at the University of California, Irvine, Dr. Anne L. Calof and her team strive to better understand the causes of developmental defects of various organ systems found in patients with Cornelia de Lange Syndrome (CdLS) and of the neural retina of the eye, as seen in those with vision problems. “During development, cells in our body know how many times to divide, what they are going to be, and when to stop,” states Project Scientist Dr. Shimako Kawauchi. “If this balance is misregulated, it can cause many problems. This is why developmental biology research is important to understand how cells decide their own fate and behavior.”
CdLS is a multi-system birth defects disorder characterized by stunted development of the overall body, patterning defects in vital organs, and deficiencies in cognitive function [1]. It is caused by a decreased amount of the Nipbl protein, which is responsible for the loading and unloading of the cohesin complex onto DNA. The cohesin complex allows DNA strands to stick together during cell division; it is also known that cohesin is involved in regulation of gene expression. The protein’s absence leads to the misregulation of genetic information. Given that almost every cell expresses Nipbl, losing it impairs development in many body systems, as was evident in zebrafish and mouse models [2,3].
The Calof lab has recently studied the effects of CdLS on heart, kidney and brain development in mice. During heart development, mice with CdLS suffer from the tissue structure failing to divide into different chambers of the heart, resulting in blood backflow and decreased blood output from the heart to the rest of the body [4]. The lab also observed size reduction as well as altered tissue structures and cellular identities in the kidneys and brains of embryonic mice [5]. Due to all these defects, it is no surprise that the majority of CdLS-afflicted mice do not live past 5-10 days after birth. The Calof lab continues to characterize the effects of Nipbl deficiency so that they may one day find a treatment for humans suffering from CdLS.
Finally, the Calof lab explores the possibility of stopping or slowing down the failure of retinal development, a condition that results in vision impairment. A null mutation, or genetic modification, in the Visual system homeobox gene 2 (Vsx2) leads to the formation of a disrupted retinal structure in both mice and humans, making it useful as a model system or a representative condition for microphthalmia [6,7]. Lately, efforts have been made to understand the impact of Growth and Differentiation Factor 11 (Gdf11), a signaling molecule involved in developmental cell regulation, in Vsx2 mutant mice [8]. By genetically manipulating mice to eliminate Gdf11 in Vsx2 mutant mice, the lab has observed rescue of the number of retinal ganglion cells, suggesting possible rescue of visual function capability [9]. Research conducted these past years have been addressing when and how reduction of Gdf11 rescues retinal cells in Vsx2 mutant models [10].
Whether it be building an embryo from scratch or an artificial placenta for premature lambs, the field of developmental biology is rapidly evolving. There is a huge interest in this field, because it allows researchers to understand how birth and developmental defects occur and eventually create future treatments for them. On the frontier of developmental neurobiology, the Calof lab as part of the CCBS continues to do their part to reach these goals.
References:
1. Krantz I.D., Mccallum J., Descipio C., Kaur M., et al.. 2004. Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nature Genetics 36: 631–5.
2. Kawauchi S., Calof A.L., Santos R., Lopez-Burks M.E., et al.. 2009. Multiple Organ System Defects and Transcriptional Dysregulation in the Nipbl /− Mouse, a Model of Cornelia de Lange Syndrome. PLoS Genetics 5.
3. Muto A., Calof A.L., Lander A.D., Schilling T.F.. 2011. Multifactorial Origins of Heart and Gut Defects in nipbl-Deficient Zebrafish, a Model of Cornelia de Lange Syndrome. PLoS Biology.
4. Santos R., Kawauchi S., Jacobs R.E., Lopez-Burks M.E., et al.. 2016. Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects. PLOS Biology 14.
5. Ha, J., Varghese R., Santos R. and Calof A.L. 2017. Unpublished data.
6. Green E.S., Stubbs J.L., Levine E.M. 2003. Genetic rescue of cell number in a mouse model of microphthalmia: interactions between Chx10 and G1-phase cell cycle regulators. Development. 130:539-52.
7. Ferda Percin E., Ploder L.A., Yu J.J., Arici K., Horsford D.J., Rutherford A., Bapat B., Cox D.W., Duncan A.M., Kalnins V.I., Kocak-Altintas A., Sowden J.C., Traboulsi E., Sarfarazi M., McInnes R.R. 2000. Human microphthalmia associated with mutations in the renal homeobox gene CHX10. Nat Genet. 25:397-401.
8. Kim J., Wu H.H., Lander A.D., Lyons K.M., Matzuk M.M., Calof A.L. 2005. GDF11 controls the timing of progenitor cell competence in developing retina. Science. 308:1927-1930.
9. Santos R, Wu J, Hamilton JA, Pinter R, Hindges R, Calof AL. 2012. Restoration of retinal development in Vsx2 deficient mice by reduction of Gdf11 levels. Adv Exp
Med Biol. 723:671-7.
10. Chang H. and Calof A.L. 2017. Unpublished data.