生醫所105-2專題演講活動，敬邀 陽明大學 生命科學系暨基因體科學研究所 范明基教授進行專題演講
演講主題為：
Functions of CDK12 in DNA damage repair and its involvement in embryonic development and neurogenesis
Abstract

The maintenance of genome integrity during early embryonic development is important to ensure the proper development of the embryo. Studies from cultured cells have demonstrated that cyclin-dependent kinase 12 (Cdk12) is a multifunctional protein that maintains genome stability. Perturbation of its functions is also known to be associated with pathogenesis and drug resistance in human cancers. However, the biological significance of Cdk12 in vivo is unclear. We demonstrated that Cdk12 depletion in mouse leads to embryonic lethality shortly after implantation. Results from an in vitro culture system of blastocysts revealed that Cdk12-/- blastocysts fail to undergo outgrowth of the inner cell mass due to an increase in the apoptosis of these cells. Spontaneous DNA damage and lower levels of DNA damage response genes, namely Atr, Brca1, Fanci and Fancd2, are detected in cultured Cdk12-/- embryos, suggesting that Cdk12 is important for the correct expression of some DNA damage response genes and indirectly has an influence on the efficiency of DNA repair.

To define Cdk12 role during neural development in vivo, we conditionally targeted Cdk12 using a Nestin-Cre mouse line (N-cKO). N-cKO mice showed microcephaly and rarely survived beyond postnatal day 0 (P0). There is reduced thickness of cortical plate layers in neocortex, and aberrant anterior commissure and corpus callosum in N-cKO due to apoptosis of newborn neural progenitors. Furthermore, birthdating experiments with EdU showed that Cdk12 not only involved in neurogenesis of neural progenitor cells, but also in neuronal migration of late-born neurons in the developing neocortex. Although 6-cortical layer organization was preserved, misaligning of layers II–IV neurons marked with CUX1 expression was observed. DiI tracing also showed a loss of the corpus callosum that is composed of axons of callosal projection neurons located in layer II/III. In short, Cdk12 function is crucial for two aspects of neuronal development, including neurogenesis and late-born neuronal migration.

Dysfunction of DNA damage response genes is correlated to tumor formation.Similarly, mutations of Cdk12 have been implicated in tumorigenesis. I would like to suggest an addition of Cdk12 and its associated cyclins into the list of the tumor gene screening panel in future precision medicine.