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Martin W. Hetzer

 

Martin W. Hetzer

Martin W. Hetzer

Professor
Jesse and Caryl Philips Foundation Chair
Molecular and Cell Biology Laboratory

"Our body's cells come in many different shapes and sizes, yet they all have one thing in common: a nucleus that houses the genome, the genetic instructions necessary for a cell to function. I am interested in how the organization and architecture of the nucleus influences gene activity and how disruption of three-dimensional order can cause developmental defects, cancer, and aging."

Ordinarily, the proteins known as nucleoporins are among the 30 gene products serving as the bricks and mortar of nuclear pore complexes, the communication channels that regulate the passage of molecules to and from a cell's nucleus. But recent research in Hetzer's laboratory suggests that some also have a second job regulating specific genes during development, and that they sometimes stray from the straight and narrow to play a role in cancer as well.

For more than a decade, scientists have known that when the nucleoporin NUP98, which should be turned off during cell differentiation, abnormally fuses with certain proteins that regulate gene expression, the marriage causes leukemia. Moreover, in many cancers, the nucleoporins NUP214 and NUP88 are misregulated and in particular are associated with very aggressive forms of lung cancer.

Investigators have long questioned why these components of the cell's transport channel are implicated in cancer and have theorized that the connection relates to a problem in the conveyance of molecules in and out of the nucleus. But Hetzer offers a different explanation. He and his team believe these proteins also function as a new class of gene transcription regulators, which turn specific genes on and off during cell differentiation or tissue development. They found that nuclear pore proteins are not only part of the transport channels but also play a role in the organization of the genome and a very direct role in gene expression.

This finding is especially significant because one of the hallmarks of cancer is abnormal organization of the cell nucleus. This nuclear pathology can be used diagnostically to determine what type of cancer someone has, but no one really knows if it is a cause or consequence of tumor formation. Hetzer and his group are now seeking a molecular understanding of aberrant nuclear organization that they hope will provide the answer.

Lab Photo

Left to right:
Front row: Martin Hetzer, Maya Capelson, Jessica Talamas, and Filipe Jacinto

Middle row: Yun Liang, Christine Doucet, Brandon Toyama, Maxi D'Angelo

Back row: Jesse Vargas, Sebastian Gomez, Robbie Schulte, Tobias Franks

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Martin W. Hetzer

Faculty

Martin W. Hetzer

Martin W. Hetzer

Professor
Jesse and Caryl Philips Foundation Chair
Molecular and Cell Biology Laboratory

Molecular and structural organization of the cell nucleus in development, aging and disease

Biogenesis of the nuclear envelope: One of the most dramatic examples of nuclear reorganization can be observed in dividing metazoan cells, in which the nucleus undergoes a cycle of complete disassembly and reformation. The assembly of the nuclear membrane is critical for proper cell cycle progression and establishing the interphase nuclear architecture. Recent studies from our lab have shown that the nuclear envelope (NE) forms by the reshaping of the endoplasmic reticulum (ER), and not as previously believed by vesicle fusion. Using live cell imaging and cell-free reconstitution systems we showed that NE formation is initiated by the binding of ER membranes to chromatin. Intriguingly, DNA-binding membrane proteins of the inner nuclear membrane, which are dispersed into the ER during mitosis, mediate the formation of a closed membrane. Many of these largely uncharacterized proteins have been shown to function in chromatin regulation and directly participate in transcription control, suggesting a mechanistic link between NE formation and post-mitotic chromatin organization.

In addition we provided new insights into the longstanding question of how NPCs are assembled. We established an in vitro assay to study NPC assembly in intact NEs and could show that pores form by a de novo process from both sides of the NE. Most recently we identified an unexpected role of ER shaping proteins in NPC assembly and succeeded in visualizing the biogenesis of single nuclear pores in living cells. The combination of these methods, together with a novel assay that is based on fluorescent nanocrystalls to study biomolecular interactions, allowed us to answer long standing questions of pore biogenesis. Most recently, we found evidence for the existence of two distinct mechanisms of NPC formation in higher eukaryotes. Our results suggest that, in organisms with open mitosis, NPCs assemble by distinct mechanisms to accommodate cell cycle-dependent differences in NE topology.

Age-related defects of nuclear pore complexes (NPCs): Changes in gene activity are part of the cellular aging process, however, the mechanisms that cause age-related alterations in gene expression are poorly understood. We have recently discovered that NPCs, essential multiprotein channels that mediate molecular trafficking between the nucleoplasm and cytoplasm of eukaryotic cells, are extremely long-lived in post-mitotic tissue and deteriorate over time causing a loss of cell compartmentalization in post-mitotic neurons. Our results suggest that nuclear pore deterioration might be a general aging mechanism leading to age-related defects in nuclear function, such as the loss of youthful gene expression programs. Age-dependent deterioration of nuclear pore complex function and the associated failure of the nuclear permeability barrier is characterized by the leaking of cytoplasmic proteins into the nucleoplasm. We detected large filaments inside the 'leaky' nuclei of old mouse and rat neurons, which stained with the cytoplasmic protein tubulin. Strikingly, tubulin-positive intranuclear structures have been linked to various neurological disorders including Parkinson's disease. Thus, nuclear pore deterioration might initiate or contribute to the onset of certain neurodegenerative diseases.

The role of the nuclear pore complex in chromatin organization and gene regulation. Recently we established a new research area in the lab that focuses on the potential role of NPC components in gene regulation. Nuclear chromatin organization plays an important but poorly understood role in the establishment and maintenance of specific gene expression programs in eukaryotic cells. Using Drosophila melanogaster as a model system we discovered an unexpected link between the dynamic organization of NPCs and gene regulation. We have detected several mobile nucleoporins at sites of on-going transcription during development. Strikingly, these chromatin-bound nucleoporins can be found inside the nucleus. Furthermore, the recruitment of nucleoporins to active sites coincides with the onset of transcription and does not depend on the presence of mRNA. Significantly, depletion of these nucleoporins by RNAi resulted in a block of transcription of nucleoporin target genes. In addition, we found a genetic interaction between several nucleoporins and the formation of silent chromatin. Chromatin binding at specific loci, not associated with gene activity, was also observed for several other dynamic nucleoporins. Based on these findings we hypothesize that mobile nucleoporins are key players in gene regulation via their association with chromatin inside the nucleus.

In summary, our results may establish a novel link between nuclear membrane formation and chromatin organization. This could provide new insights into the well-known phenomenon of pathological nuclear architecture and the physiological consequences of aberrant nucleoporin expression observed in various cancer cells. Ultimately, our studies will lead to a better understanding of developmental gene expression and we hope to translate this knowledge into novel strategies to detect nuclei exhibiting aberrant gene activity and to control expression of disease-associated genes.

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