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Martin W. Hetzer

 

Martin W. Hetzer

Martin W. Hetzer

Hearst Endowment Associate Professor
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 premature aging."

Cell division, or mitosis, in multicellular animals involves the wholesale disruption of normal cellular architecture to allow for successful partitioning of cellular components to each daughter cell. Probably the most dramatic event is the reformation of the nuclear envelope, a highly structured barrier that separates the nuclear genome from the rest of the cell. But just how a dividing cell rebuilds the nuclear envelope, the protective, functional wrapping that encases both the original and newly copied genetic material, has been a source of controversy for the last 20 years. Just as chromosomes duplicate, the endoplasmic reticulum, or ER, an intracellular labyrinth of interconnected tubes and sheets contiguous with the nuclear membrane, also reproduces itself. In a mature cell the ER works closely with the genome, synthesizing and transporting the proteins produced under the direction of genes housed inside the nucleus.

Hetzer and his team used a popular scientific model of mitosis, the eggs of Xenopus, an African frog, to determine how the nuclear envelope is restored following the replication and separation of chromosomes. By quantifying images produced using time-lapse microscopy, they observed that, during the early phases of mitosis, the tubules of the ER bind directly to DNA found at the surface of the chromatin, the tightly bundled coil of genetic material and proteins that form chromosomes after DNA replication. Then, as mitosis proceeds, extra DNA binding proteins are employed to progressively immobilize some of the tubules, flattening them out to form a double-sided sheet, which then bends around what will become the nucleus.

Disruption of the nuclear order compromises the integrity of highly differentiated cells and commonly leads to cancer and other serious problems. The Hutchinson- Gilford progeria syndrome, for example, is caused by a defect in the nuclear membrane that disrupts the nuclear architecture and leads to a disease that resembles aspects of normal human aging, such as premature loss of hair, restricted joint mobility, and atherosclerosis. There are early hints that normal human aging is also accompanied by changes in the three-dimensional organization of the nucleus.

Lab Photo

Left to right:
Martin Hetzer, Maxi D'Angelo, Robbie Schulte, Maya Capelson, Sebastian Gomez, Jesse Vargas, Jessica Talamas, Christine Doucet, Yun Liang

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Martin W. Hetzer

Faculty

Martin W. Hetzer

Martin W. Hetzer

Hearst Endowment Associate Professor
Molecular and Cell Biology Laboratory

Biogenesis of the cell nucleus

During eukaryotic cell division the complex architecture of the cell nucleus breaks down to allow chromosomes to be captured by the mitotic spindle, which then accurately partitions them to daughter cells. Once segregation is accomplished, the interphase architecture is re-established by unknown mechanisms to enable perpetuation of genomic information.

The most dramatic events during nuclear assembly is the reformation of the nuclear envelope, a highly structured barrier that separates the nuclear interior from the rest of the cell. It is composed of a concentric double membrane that is penetrated by nuclear pores, which serve as channels for transport between the nucleus and the cytoplasm.

The Hetzer Laboratory is focusing on understanding the molecular basis of nuclear assembly and its regulation during cell division. Currently Hetzer's lab uses live cell imaging and biochemistry as well as genetic and computational approaches to study various aspects of nuclear formation.

Dynamic changes of the nuclear envelope during cell differentiation

The nuclear envelope undergoes dramatic structural changes during cell differentiation. Mutations in nuclear envelope proteins cause a variety of different human diseases, highlighting the importance of the nuclear envelope for cell function. Mammalian nuclei are complex organelles, whose functions depend largely on a spatial, higher order organization of chromatin. Anchorage of chromatin at the nuclear periphery and its three-dimensional organization within the nuclear interior may regulate cell type- and differentiation-specific gene expression.

We are studying the dynamic reorganization of the nuclear envelope during muscle- and neuronal differentiation. Additionally, we are using Drosophila and C. elegans as model systems to identify functional interactions between the nuclear periphery and chromatin.

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