PMID- 36078134
OWN - NLM
STAT- MEDLINE
DCOM- 20220913
LR  - 20221126
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 11
IP  - 17
DP  - 2022 Sep 1
TI  - A Zebrafish/Drosophila Dual System Model for Investigating Human Microcephaly.
LID - 10.3390/cells11172727 [doi]
LID - 2727
AB  - Microcephaly presents in neurodevelopmental disorders with multiple aetiologies, 
      including bi-allelic mutation in TUBGCP2, a component of the biologically 
      fundamental and conserved microtubule-nucleation complex, gamma-TuRC. Elucidating 
      underlying principles driving microcephaly requires clear phenotype 
      recapitulation and assay reproducibility, areas where go-to experimental models 
      fall short. We present an alternative simple vertebrate/invertebrate dual system 
      to investigate fundamental TUBGCP2-related processes driving human microcephaly 
      and associated developmental traits. We show that antisense morpholino knockdown 
      (KD) of the Danio rerio homolog, tubgcp2, recapitulates human TUBGCP2-associated 
      microcephaly. Co-injection of wild type mRNA pre-empts microcephaly in 55% of KD 
      zebrafish larvae, confirming causality. Body shortening observed in morphants is 
      also rescued. Mitotic marker (pH3) staining further reveals aberrantly 
      accumulated dividing brain cells in microcephalic tubgcp2 KD morphants, 
      indicating that tubgcp2 depletion disrupts normal mitosis and/or proliferation in 
      zebrafish neural progenitor brain cells. Drosophila melanogaster double knockouts 
      (KO) for TUBGCP2 homologs Grip84/cg7716 also develop microcephalic brains with 
      general microsomia. Exacerbated Grip84/cg7716-linked developmental aberration 
      versus single mutations strongly suggests interactive or coinciding gene 
      functions. We infer that tubgcp2 and Grip84/cg7716 affect brain size similarly to 
      TUBGCP2 and recapitulate both microcephaly and microcephaly-associated 
      developmental impact, validating the zebrafish/fly research model for human 
      microcephaly. Given the conserved cross-phyla homolog function, the data also 
      strongly support mitotic and/or proliferative disruption linked to aberrant 
      microtubule nucleation in progenitor brain cells as key mechanistic defects for 
      human microcephaly.
FAU - Bartoszewski, Slawomir
AU  - Bartoszewski S
AD  - Department of Biology, Institute of Biology and Biotechnology, University of 
      Rzeszow, 35-601 Rzeszow, Poland.
FAU - Dawidziuk, Mateusz
AU  - Dawidziuk M
AUID- ORCID: 0000-0001-5102-8722
AD  - Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, 
      Poland.
FAU - Kasica, Natalia
AU  - Kasica N
AUID- ORCID: 0000-0002-0242-2587
AD  - Department of Animal Anatomy, Faculty of Veterinary Medicine, University of 
      Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland.
FAU - Durak, Roma
AU  - Durak R
AUID- ORCID: 0000-0001-9100-766X
AD  - Department of Biology, Institute of Biology and Biotechnology, University of 
      Rzeszow, 35-601 Rzeszow, Poland.
FAU - Jurek, Marta
AU  - Jurek M
AD  - Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, 
      Poland.
FAU - Podwysocka, Aleksandra
AU  - Podwysocka A
AD  - Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, 
      Poland.
FAU - Guilbride, Dorothy Lys
AU  - Guilbride DL
AD  - Independent Researcher, Manhica MPT 1122, Mozambique.
FAU - Podlasz, Piotr
AU  - Podlasz P
AUID- ORCID: 0000-0002-9162-5449
AD  - Department of Pathophysiology, Forensic Veterinary Medicine and Administration, 
      Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, 
      10-719 Olsztyn, Poland.
FAU - Winata, Cecilia Lanny
AU  - Winata CL
AUID- ORCID: 0000-0002-7718-5248
AD  - Laboratory of Zebrafish Developmental Genomics, International Institute of 
      Molecular and Cell Biology in Warsaw, 02-109 Warsaw, Poland.
FAU - Gawlinski, Pawel
AU  - Gawlinski P
AUID- ORCID: 0000-0002-3672-5834
AD  - Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, 
      Poland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220901
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
SB  - IM
MH  - Animals
MH  - Drosophila
MH  - Drosophila melanogaster
MH  - Humans
MH  - *Microcephaly/genetics
MH  - Reproducibility of Results
MH  - Zebrafish/genetics
PMC - PMC9455030
OTO - NOTNLM
OT  - Drosophila
OT  - TUBGCP2
OT  - microcephaly
OT  - microtubules
OT  - zebrafish
COIS- The authors declare no conflict of interest.
EDAT- 2022/09/10 06:00
MHDA- 2022/09/14 06:00
PMCR- 2022/09/01
CRDT- 2022/09/09 01:13
PHST- 2022/08/14 00:00 [received]
PHST- 2022/08/27 00:00 [revised]
PHST- 2022/08/28 00:00 [accepted]
PHST- 2022/09/09 01:13 [entrez]
PHST- 2022/09/10 06:00 [pubmed]
PHST- 2022/09/14 06:00 [medline]
PHST- 2022/09/01 00:00 [pmc-release]
AID - cells11172727 [pii]
AID - cells-11-02727 [pii]
AID - 10.3390/cells11172727 [doi]
PST - epublish
SO  - Cells. 2022 Sep 1;11(17):2727. doi: 10.3390/cells11172727.