Michael Piper

Understanding the drivers of neural stem cell differentiation

What are the mechanisms that control neural stem cell (NSC) differentiation during embryogenesis, and that enable the generation of the diverse suite of neurons and glia that comprise the brain? This is a key question in developmental neuroscience. My contribution to this field to date has been to reveal central transcriptional regulators that mediate NSC biology within the brain. Using rodent model systems, I demonstrated that transcription factors of the Nuclear Factor One (NFI) family mediate NSC proliferation and differentiation in the embryonic, postnatal and adult nervous system. This work has received international recognition, as evidenced by numerous invited international presentations and high-impact reviews (e.g. Trends in Cell Biology), and forms the framework around which the hypotheses of this program will be addressed.

I am interested in defining how NSC proliferation and differentiation is regulated at a transcriptional and epigenomic level within the developing nervous system. Using the developing mouse brain as a model system, we are using a suite of molecular and cellular techniques to understand how diverse regions of the nervous system are generated, including the cerebral cortex, the cerebellum, the spinal cord and the hypothalamus. For example, within the cerebral cortex, we are investigating how the NFI family of transcription factors mediate NSC differentiation, and how mutations to the NFI family culminate in macrocephaly, and disorders such as Malan syndrome. Moreover, we are using mice lacking the gene Nsd1(a histone modifying protein) to investigate the development of a human syndrome known as Sotos syndrome, which is also characterised by macrocephaly. In collaboration with Mikael Boden (SCMB), we are also investigating how changes to chromatin landscapes mediate NSC differentiation, and developing bioinformatic tools to enhance the analysis of RNA-seq and ChIP-seq datasets. Collectively, this work will provide fundamental insights into neural development, as well as insights into human neurodevelopmental disorders that arise as a result of abnormal neural stem cell biology in utero.

Adult neurogenesis

The birth of new neurons within the mature cerebral cortex, a process termed neurogenesis, plays a critical role in learning, memory and spatial navigation. We are investigating various aspects of adult neurogenesis in rodent models, such as neural stem cell quiescence . We are also interrogating the consequences of abnormal neurogenesis using behavioural tests for learning and memory.

We employ a range of transgenic mice to investigate adult neurogenesis, coupled with techniques ranging from immunocytochemistry, behavioural testing, analysis of axonal connectivity and genome-wide sequencing platforms. Given the critical roles that learning and memory play in our everyday lives, and the fact that neurogenesis within the adult brain diminishes with age, this research will provide fundamental insights into how this vital process is co-ordinated at a cellular and molecular level.

Identifying how abnormal neural stem cell biology contributes to disease

The importance of NSC biology to brain development is underscored by disorders associated with abnormal NSC differentiation, including autism, hydrocephalus and macrocephaly. Despite the role of aberrant NSC development to these disorders, our understanding of the cellular and molecular deficits that contribute to disease onset and progression remains limited. Recently, my work has begun to focus on these disorders. Moreover, as the transcriptional landscape of many cancers resembles that of stem cells during development, I am also applying my expertise to understand how abnormal transcriptional activity contributes to cancer progression. This approach has gained significant traction, as evidenced by international awards (2015 Innovator Award, Hydrocephalus Association) and grants (Simons Foundation Autism Research Initiative, 2018-2019; Cancer Council Queensland, 2016-2017) I have received.

Understanding the drivers of neural stem cell differentiation

What are the mechanisms that control neural stem cell (NSC) differentiation during embryogenesis, and that enable the generation of the diverse suite of neurons and glia that comprise the brain? This is a key question in developmental neuroscience. My contribution to this field to date has been to reveal central transcriptional regulators that mediate NSC biology within the brain. Using rodent model systems, I demonstrated that transcription factors of the Nuclear Factor One (NFI) family mediate NSC proliferation and differentiation in the embryonic, postnatal and adult nervous system. This work has received international recognition, as evidenced by numerous invited international presentations and high-impact reviews (e.g. Trends in Cell Biology), and forms the framework around which the hypotheses of this program will be addressed.

I am interested in defining how NSC proliferation and differentiation is regulated at a transcriptional and epigenomic level within the developing nervous system. Using the developing mouse brain as a model system, we are using a suite of molecular and cellular techniques to understand how diverse regions of the nervous system are generated, including the cerebral cortex, the cerebellum, the spinal cord and the hypothalamus. For example, within the cerebral cortex, we are investigating how the NFI family of transcription factors mediate NSC differentiation, and how mutations to the NFI family culminate in macrocephaly, and disorders such as Malan syndrome. Moreover, we are using mice lacking the gene Nsd1(a histone modifying protein) to investigate the development of a human syndrome known as Sotos syndrome, which is also characterised by macrocephaly. In collaboration with Mikael Boden (SCMB), we are also investigating how changes to chromatin landscapes mediate NSC differentiation, and developing bioinformatic tools to enhance the analysis of RNA-seq and ChIP-seq datasets. Collectively, this work will provide fundamental insights into neural development, as well as insights into human neurodevelopmental disorders that arise as a result of abnormal neural stem cell biology in utero.