CMMT Newsletter September 2023

Dr. Daniel Goldowitz: Bringing it together 

Dr. Daniel Goldowitz has made many significant contributions to the field of developmental neurogenetics over the course of his extensive career. And he is by no means done yet. Through his research at his lab at the CMMT and BCCHRI, he has spent the past 15 years studying the gene regulatory networks that are key to making up the cerebellum. Using molecular and bioinformatic technologies to investigate various expressions of genes and how they connect with one another to create gene regulatory networks, he has discovered new genes that were not previously seen to have been involved in the development of the cerebellum. These discoveries could provide therapeutic targets for disabilities such as autism, schizophrenia, and developmental coordination disorders, among other conditions.

“The cerebellum is, to my mind, the central place in coordinating brain activity in general,” Dr. Goldowitz said. “We’re learning root elements from our studies of the whole to deconstruct these complex disabilities and understand them. Ultimately, we would like to take what we’re doing at the bench to the bedside.”

Dr. Goldowitz’s recent work around the PAX6 gene is a case in point. Previously identified as a master control gene in the development of the eye and pancreas, PAX6 has now been found to be expressed in the cerebellum. In evaluating the functions of PAX6, Dr. Goldowitz and his team determined that the absence of PAX6 is associated with the down regulation of three sets of neurons, namely unipolar brush cells, cerebellar nuclear neurons, and granular cells.  Each of these sets of genes is identifiable with a particular region of the cerebellum. “We then found that they were all perturbed in very specific ways,” Dr. Goldowitz said. “One had a migration problem, another had a cell death problem, and the other had a developmental delay problem.” This showed that PAX6 is being regulated differently in all three cell types, however the commonality between the cell types is that they are all regulated by glutamate. “This is one population of cells that is the excitatory network in the cerebellum,” Dr. Goldowitz said. “So we go from genes to cells to the functional workings of the cerebellum.  If you excite elements in the cerebellum, they engage the glutamatergic system. This becomes relevant to a disorder like autism, which is seen as a disorder of excitation and inhibition,” he said.

Further investigations looking into upregulated genes led Dr. Goldowitz and his team to discover the gene WLS, which turned out to be an entirely new marker for cells of the glutamatergic lineage.  “It’s interesting but not surprising that all cells of the glutaminergic lineage in the cerebellum come from a very specific progenitor zone called the Rhombic Lip,” Dr. Goldowitz said. “We found that the WLS gene is a really key marker for the early development of the cells of the Rhombic Lip. As we explored this further, we began to appreciate that this gene is key to gene regulatory networks, and that if you perturb these networks, you perturb the cells involved in the rhombic lip as well as all the molecules that make up the expression patterns of the cells that emerge from the rhombic lip,” he said.

“Very recently several groups have shown that the most common form of pediatric brain tumour is the medullablastoma, which has its origin in the rhombic lip. So people describe the medulloblastoma as a dysfunction of the rhombic lip,” Dr. Goldowitz said. “The discovery of WLS is another example of how our research into gene regulatory networks in the very early development of the cerebellum has led directly to a human condition that we hope we can find interventions for at the molecular level, in order to stop the uncontrolled proliferation of cells that are the basis of the medulloblastoma,” Dr. Goldowitz said.

Most recently, Dr. Goldowitz, together with Tim F. Oberlander, Jerome Y. Yager, and David D. Eisenstat, published a textbook entitled Neurodevelopmental Pediatrics. “It’s the effort to bring together all the elements of the genetics and the environment from animal models to human beings. This book emerged from the Kid’s Brain Health Network – a bench to bedside effort,” Dr. Goldowitz said.

Dr. Goldowitz credits the interconnectivity in the larger neurodevelopmental community for making the book possible. Similarly, the community within the CMMT and BCCHR is also key and to that end Dr. Goldowitz is looking forward to the resuscitation of Friday afternoon get togethers at the CMMT. “It has been challenging during the prior two years,” he said. “Some labs had closed [due to covid]. The community was strained and stressed. We’re now working on putting together the CMMT Work In Progress (talks).” 

Initially led by Dr. Elizabeth Simpson, then Dr. Goldowitz, then Dr. Stefan Taubert, the Friday afternoon get togethers began at the CMMT before moving to the BCCHRI. “They were a really fun event,” Dr. Goldowitz said. “They involved beer, treats and great talks from students and post doctorate fellows, and faculty. Historically, that was how we helped seed a community at BCCHR and CMMT.” Today, the CMMT Trainee Committee, led by Dr. Bruce Verchere and Evelyn Lomba, continues to build community through the initiative of the CMM Talks series and possibly the annual, in person Christmas party. “We can do a great job with Bruce’s lead, and our active faculty, students, and post-doctoral fellows. The department of Medical Genetics has also been doing a great job of bringing people together at the BCCHR.”

Dr. Goldowitz is an Investigator at BC Children’s Hospital, a Senior Scientist, at the Centre for Molecular Medicine and Therapeutics, and a former Canada Research Chair, Tier 1.
Academic Affiliations
Professor, Department of Medical Genetics, Faculty of Medicine, University of British Columbia
Major achievements
Scientific Director, NeuroDevNet (funded by Networks of Centres of Excellence) – 2009 ~ 2014, 2014 – 2019 and co-founder of CHILD-BRIGHT, a Network of the CIHR-funded Strategies inPatient-oriented Research
President, International Behavioural and Neural Genetics Society – 2007
Canadian Research Council Chair in Developmental Neurogenetics, Tier 1 – 2007 – 2014, 2014 – 2021

Congratulations to Drs. Poul Sorensen, Eitan Prisman and Seth Parker – recipients in the 2023 Terry Fox New Frontiers Program Project Grants competition

Five Canadian research teams will receive a total of $12 million to advance cancer research and treatment following new awards in the 2023 Terry Fox New Frontiers Program Project Grant (PPG) competition.  Each project will receive $2.4 million over a period of four or five years.  The Lotte & John Hecht Memorial Foundation will co-fund three of the projects by providing a total of $3.6 million. 
All five teams are new to the Terry Fox Research Institute (TFRI) research portfolio.  Their focus will be on oral, lung, prostate, ovarian and pancreatic cancers, as well as sarcomas and neuroendocrine tumours.  The three teams located in British Columbia will be led by Drs. Eitan Prisman (University of British Columbia); Julian Lum (BC Cancer, University of Victoria); and Stephen Lam and William Lockwood (BC Cancer).  Along with Dr. Prisma, UBC researchers Drs. Poul Sorensen and Seth Parker will make significant contributions to this groundbreaking cancer research.

Advancing tools and techniques for virtual surgical planning (VSP) and the personalized treatment of patients with oral cancers 

With co-funding from the Lotte & John Hecht Memorial Foundation, Dr. Eitan Prisman, clinical associate professor at the University of British Columbia, will use his new PPG to lead a team of multidisciplinary researchers looking to develop advanced surgical planning and intraoperative tools to enhance outcomes for patients undergoing mandibular (jawbone) reconstructive surgeries due to oral cancer. “This generous support will allow us to further optimize care and quality of life for patients with oral cancer and oral diseases across Canada,” says Dr. Prisman.

Through the use of high-end, state-of-the-art visual imaging technologies to capture pictures, the team hopes to see clues to the origins and behaviour of cancer. 
Drs. Poul Sorensen and Seth Parker will focus on studying how tumour cells cope with metabolic stress, in specific types of cancer, like pancreatic cancer and Ewing sarcoma. Using advanced mass spectrometry imaging techniques, the researchers will measure changes in the tumour’s nutrient composition and how this affects surrounding immune cells within the tumour.

2023 UBC Gairdner Dinner

Schaffner S.L., Wassouf Z., Hentrich T., Nuesch-Germano M., Kobor M.S., and Schulze-Hentrich, J.M. (2023) Distinct Impacts of Alpha-synuclein Overexpression on the Hippocampal Epigenome of Mice in Standard and Enriched Environments. Neurobiol Dis. 186:106274.
Duarte F, Vachey G, Caron NS, Sipion M, Rey M, Perrier AL, Hayden MR, Déglon N. Limitations of dual-
sgRNA CRISPR strategies for the treatment of CNS genetic disorders. Hum Gene Ther. 2023 Sep 2. 2023 Sep 2. doi: 10.1089/hum.2023.109. Online ahead of print. PMID: 37658843
Mehta N, Gilbert R, Chahal PS, Moreno MJ, Nassoury N, Coulombe N, Lytvyn V, Mercier M, Fatehi D, Lin
W, Harvey EM, Zhang L, Nazemi-Moghaddam N, Mehdy Elahi S, Ross CJD, Stanimirovic DB, Hayden MR. Preclinical Development and Characterization of Novel Adeno-Associated Vectors for the Treatment of Lipoprotein Lipase Deficiency. Hum Gene Ther. 2023 Aug 19. doi: 10.1089/hum.2023.075. Online ahead of print. PMID: 37597209
Aly AE, Caron NS, Findlay-Black H, Schmidt ME, Anderson C, Ko S, Baddeley HJE, Anderson L, Casal LL, Rahavi RSM, Martin DDO, Hayden MR. Mutant huntingtin-lowering antisense oligonucleotide delivery to the brain using intranasal apolipoprotein A-I nanodiscs for treatment of Huntington disease. J Control Release. 2023 Jul 17:S0168-3659(23)00451-0. Online ahead of print. PMID: 37468110

Ferrari Bardile C, Radulescu CI, Pouladi MA, 2023. Oligodendrocyte pathology in Huntington’s disease: from mechanisms to therapeutics. Trends Mol. Med PMID: 37591764 
Ozgoren OK, Sequiera GL, Ferrari Bardile C, Gjervan SC, Salman A, Lehman A, Turvey SE, Ross CJD, Stockler S, Pouladi MA. Generation of a human induced pluripotent stem cell line from a patient with hypomyelinating leukodystrophy 22 (HLD22). Stem Cell Res. 2023 Jul 28;71:103174. doi: 10.1016/j.scr.2023.103174. Online ahead of print. PMID: 37531724
Tano V, Utami KH, Yusof NABM, Bégin J, Tan WWL, Pouladi MA, Langley SR. Widespread dysregulation of mRNA splicing implicates RNA processing in the development and progression of Huntington’s disease. EBioMedicine. 2023 Aug;94:104720. doi: 10.1016/j.ebiom.2023.104720. Epub 2023 Jul 21.
Petrozziello T, Huntress SS, Castillo-Torres AL, Quinn JP, Connors TR, Auger CA, Mills AN, Kim SE, Liu S, Mahmood F, Boudi A, Wu M, Sapp E, Kivisäkk P, Sunderesh SR, Pouladi MA, Arnold SE, Hyman BT, Rosas HD, DiFiglia M, Pinto RM, Kegel-Gleason K, Sadri-Vakili G. Age-dependent increase in tau phosphorylation at serine 396 in Huntington’s disease pre-frontal cortex. Journal of Huntington’s Disease. 2023. In press.

The Edwin S.H. Leong Centre for Healthy Aging is hosting an upcoming symposium at the University of British Columbia from November 19th-20th, 2023 that your members may be interested in. The symposium is called Aging Better Together: Collaborating to Improve Outcomes across British Columbia and will bring together researchers, trainees, and stakeholders to provide a holistic and interdisciplinary perspective on aging.
The two-day event will feature oral presentations, a poster session, interactive panel discussions, and networking. To facilitate knowledge exchange and collaborations, the symposium will feature just one session at a time. We are pleased to feature keynote presentations by:
 Dr. Parminder Raina, Professor, Department of Health Research Methods, Evidence and Impact, McMaster University; Lead Principal Investigator, Canadian Longitudinal Study on Aging; Canada Research Chair in Geroscience; and Scientific Director, McMaster Institute for Research on Aging 
Dr. Raphaële Castagné, Center for Epidemiology & Research in Population Health, University of Toulouse III Paul Sabatier, INSERM, France
You can find more information about the symposium, including instructions for registering and submitting abstracts, here:

Awards & Congrats
Paula Littlejohn
BC Children’s Hospital Research Institute Healthy Starts Postdoctoral Fellowship

Mandy Meijer
‘Society to Cell’ Clyde Hertzman Memorial Fellowship

Erick Navarro
UBC Bioinformatics Graduate Program Four Year Doctoral Fellowship

Karlie Edwards
BC Graduate Scholarship

Michael Ke
BC Graduate Scholarship

Chiaki Shuzenji
BCCHR Healthy Starts Master’s Studentship

Ryan McCallum
BC Graduate Scholarship

Glen Sequiera
Michael Smith Health Research BC Fellowship

Dr. Michael R. Hayden
2023 Lifetime Achievement Award, Huntington Study Group, USA
Elsevier – Best Research Paper Award, XXVI World Congress of Neurology, Montreal, Canada
25th Annual Life Sciences BC Award for Companies of Year

Dr. Daniel Goldowitz
BC SPOR Support Unit – Patient Experience Library

Best Research Paper
The Cerebellum is pleased to highlight the best research paper of 2022 as selected by the editorial board:
Miguel Ramirez et al. The Cerebellar Gene Database: a Collective Database of Genes Critical for Cerebellar Development. DOI 10.1007/S12311-022-01445-W.

Congratulations to Drs. Eitan Prisman and Seth Parker: one of five new research teams named recipients of the 2023 Terry Fox New Frontiers Program Project Grants:

Fun Facts
The tallest man ever recorder was American giant Robert Wadlow (1918-1940) who stood 8 feet 11 inches. Wadlow’s size was the result of an abnormally enlarged pituitary gland.

The oldest person ever to have lived (whose age could be authenticated), a French woman named Jeanne Louise Calment, was 122 years old when she died in 1997.

The Four Corners is the only spot in the US where you can stand in four states at once: Utah, Colorado, Arizona and New Mexico.

The oldest known living land animal is a tortoise named Jonathan, who turned 190 years old in 2022 and is currently living in the Atlantic Ocean since 1982 from the island of St. Helena (born in 1832).

The heart of the blue whale, the largest animal on earth, is five feet long and weighs 400 pounds. The whale in total weighs 40,000 pounds.

Our next newsletter will be released March 2024.
Submit storyline suggestions to by March 1, 2024. 
Submit awards, events, publications, kudos, etc. to by March 15, 2024


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