Charles E. Lytle Jr. Research Professorship in Pediatrics Catherine E.H. Keegan, M.D, Ph.D. Wednesday, September 9, 2020 Kahn Auditorium.
– Good evening, everyone.
For those of you who
don't already know me,
my name is Dr. Carol Bradford.
I serve as a Professor of Otolaryngology
and as the immediate
past Executive Vice-Dean
for Academic Affairs.
I have accepted a role to serve
as Dean of the College of Medicine
at the Ohio State University
effective October 1st, 2020.
It has been a true
privilege to participate
in many, many professorship ceremonies
over the last four plus years.
This celebration will
actually be the last one
I participate in before my departure.
I do hope to continue on a long legacy
at the University of Michigan in service
as an Emeritus Faculty Member.
Welcome colleagues, family, and friends
to our virtual celebration
of the Charles E. Lytle
Junior Research,
Professorship and Pediatrics.
We are grateful to
everyone who is joining us
for this very, very special event,
which we are streaming live
from the Khan Auditorium
in the A. Alfred Taubman
Biomedical Science
Research Building today.
This evening, we are here to
celebrate the installation
of Dr. Catherine Keegan as the first ever
Charles E. Lytle Junior Research
Professorship in Pediatrics
at the University of Michigan.
This professorship was made
possible through the generosity
and foresight of Charles E. Lytle Jr.
for which we are very, very grateful.
More than 40 years ago,
Mr. Lytle set up a Trust
for his daughter Margaret,
to make sure that she
would be looked after
and receive the care she
needed after he passed away.
in that Trust agreement,
Mr. Lytle stipulated
that any funds remaining
from that Trust after Margaret passed away
would go to the University
of Michigan Medical School
to be used for medical
research of epilepsy,
cerebral palsy and
developmental disorders.
After ensuring that his
daughter would be cared for
Mr. Lytle wanted to make a difference
for other children and families
finding cures for these
conditions to give children
more hope and a better quality of life.
Mr. Lytle's generosity
is making an incredible
difference to this date
and will continue to do so
at the University of Michigan.
In addition to the professorship now held
by Dr. Keegan that we
are celebrating today,
Mr. Lytle's gift is supporting
Michigan Medicine researchers
studying cerebral palsy,
epilepsy, and pediatric diseases.
His philanthropic gift also established
the Charles E. Lytle Junior
Research Professorship
in Physical Medicine and Rehabilitation.
Mr. Lytle's generosity will
deliver the critical support
that Dr. Keegan needs
to pursue the project
and research that can truly
change and improve lives.
This support will help Dr. Keegan to drive
innovative ideas and exciting
research that can impact
and enhance the way we deliver care.
An endowed Professorship is a very,
very prestigious recognition.
And I welcome Dr. Keegan's family members
as they watch online and
joining us today in person,
are Dr. Keegan's family, her husband Mike,
her daughter, Carly and her son, Michael,
and we are all socially
distanced in the auditorium
and only removing our
masks for public speaking.
We are so glad that you can
be here in person to celebrate
and mark this very, very special moment.
Dr. Keagan's research centers
on mechanisms that lead
to birth defects of the
spine, gastrointestinal tract,
urinary system, and other
areas of the lower body.
She also looks at how irregularities
and chromosome structures
can cause certain traits
or characteristics in humans.
Her work shares hope
and incredible promise
for families seeking diagnoses,
more effective therapies
or greater understanding of birth defects
and genetic conditions that
are impacting their son
or daughter's quality of life.
Next, it is my true pleasure
and honor to introduce to you
Dr. Donna Martin, the Ravitz Foundation
Endowed Professor of Pediatrics
and Communicable Diseases
and Chair of the Department of Pediatrics
and Professor of Pediatrics
and Human Genetics
in the Medical School, Dr. Martin.
– Thank you, Dr. Bradford
for that introduction.
It is my distinct honor
to present Dr. Catherine Katie Keegan,
my friend and colleague,
as the Charles E. Lytle Junior Research
Professor in Pediatrics.
Dr. Keegan received her Bachelor's degree
in Cell and Molecular Biology
at the University of Michigan.
As an undergraduate student,
she worked in the laboratory
of Dr. David Ginsburg
studying Immunoglobulin Rearrangements
in Hodgkin's disease.
Her experience in the laboratory
inspired her to pursue
MD-PhD training through the University
of Michigan MSTP program.
Dr. Keegan's PhD training
in Sally Camper's laboratory
and the CMB program
focused on corticotropin-releasing hormone
sequencing and expression
in the mouse brain.
After graduate training,
Katie moved to Boston Children's Hospital
for pediatric residency.
During which time she did
research with Dr. Bruce Korf
on the role of the cell one
gene in Townes-Brocks syndrome.
She then moved back to
the University of Michigan
for Medical Genetics Residency,
where she eventually joined the laboratory
of Dr. Gary Hammer studying SF-1
in the Biology of the adrenal gland.
During this time,
Katie identified the ACD
gene and defined its roles
in caudal, dysplasia
and telomere integrity.
She then established her own laboratory
as a junior faculty member,
focusing on human
conditions with disrupted
development of caudal structures,
including the genital
urinary tract and disorders
of sexual development.
Dr. Keegan has been widely
recognized for her work.
She is an elected member
of the American Society
of Clinical Investigation,
the American Pediatric Society,
and the Society for Pediatric Research.
She is an internationally
recognized expert
in mammalian birth defects.
And her laboratory has
been funded by the NIH,
the March of Dimes, the
American Cancer Society
and the Endocrine Society.
In service, Dr. Keegan
has served for nine years
as Education Lead for Pediatric Genetics
and as a Medical Director for
the Genetic Counseling Program
from 2001 to 2016.
Since 2016, she has served as Director
of the Medical Genetics Residency Program.
And more recently directs the
combined Pediatric Genetics
and Medical Biochemical
Genetics Residency Programs.
Katie also served as Associate
Director for the MSTP program
for eight years, from 2012 through 2020
and from 2017 was a member
of the Advisory Committee
on appointments, promotion and tenure
serving as its chair from 2018 to 2019.
In 2017, she participated
in the Rudi Ansbacher
Women in Academic Medicine
Leadership Scholars Program.
It is no surprise that her accomplishments
span the clinical, educational, research
and service missions of our institution.
And she has contributed in
lasting and meaningful ways
to Michigan Medicine
and the International Medical Community.
She has and will continue
to make us all very proud
and I couldn't be more proud
to be here representing you.
Thank you.
– Thank you for those gracious
and well-deserved
comments about Dr. Keegan.
Next, it's my pleasure to
introduce Dr. Jeffrey Ennis,
the Morton S and Henrietta K. Sellner
Professor of Human Genetics,
Professor of Pediatrics
and Internal Medicine
and Chief of the Division of
Pediatric Genetics Metabolism
and Genomic Medicine
in the Department of
Pediatrics, Dr. Ennis.
– Thank you, Carol.
I am particularly proud
to be able to witness
Dr. Keegan being named the
Charles E. Lytle Junior Research
Professor in Pediatrics.
Dr. Keegan is a wonderful
physician scientist.
And my relationship with
her began many years ago
during her MD and her PhD training here
at the University of Michigan.
And I'm excited that she has
achieved this accomplishment.
A reflection of a tireless research
and wonderful citizenship
for Michigan medicine.
I was thrilled and fortunate
to recruit Dr. Keegan back
to the University of Michigan
from Boston, where she was completing
her pediatric residency
into the second class
in 1999 to 2001 of the Medical
Genetics Residency Program,
along with Dr. Martin.
I had the hope that Katie
would develop a successful
research career exploring the genetics
of human birth defects,
and she chose to focus
on caudal malformations
using mouse models, as well as
disorders of sex development,
but that's not all.
She's done exceptionally well
publishing well over 60 manuscripts
and becoming Professor of Pediatrics
and Professor of Human Genetics in 2019.
Of her many research discoveries,
which I won't go into all of them,
it was particularly fun when
we were simultaneously studying
two different mouse mutants each secondary
to early transpose on insertion mutations,
mine on the X chromosome are polypodia
resulted in altered MAP kinase activity
and malformations with multiple
legs, a caudal malformation,
and Katie studying Danforth's Short Tail,
which she'll, I think
describe perhaps today
in more detail is an early
transpose on insertion
in the chromosome that
activates the expression
of a gene PTF1A in caudal
structures of the embryo,
where it's not supposed to be expressed,
and which causes a disruption
in another critical pathway
of hedgehog signaling.
Her research includes many other
outstanding accomplishments
in other models of human malformations,
including the adrenal cortical
dysplasia mouse mutant,
as mentioned by Donna and in
disorders of sex development.
I have been proud to be a
co-investigator with her
on six manuscripts over her career so far.
Spanning HOXA13 polyalanine
expansion mutations,
craniofacial did
synostosis, XY sex reversal,
Oculo dental digital dysplasia
and trap seven gene
related human disorders.
These accomplishments
illustrate the breadth
of Dr. Keagan's research
endeavors and importantly,
to keep it all in perspective,
all of this work that she accomplishes
benefits the patients and the families
who are afflicted with these disorders
and represents what's in her heart.
Dr. Keegan has always been
an outstanding citizen
in our departments.
When I started the Medical
Genetics Residency Program,
we weren't aware that someday
there would be multiple
Genetics Residency Training Programs.
However, Dr. Kagan is now the Director
of three ACGME accredited
Training Programs
in Medical Genetics, all with trainees.
And she has done a superb
job with all phases,
including recruitment, which
we are actively involved with
right now, as well as the oversight
that's required for proper
training and maintenance
and improvement of the
training environment.
I always find it exciting
to listen to Katie speak
at our clinical conferences,
particularly our Medical
Genetics Grand Rounds,
because she explains
the clinical condition
and ties it together
with the Basic Science
Genetics together so well.
I always remember these presentations,
particularly while I'm in
clinic looking at patients.
I can see Katie pointing out
very distinctive features
in her presentation.
And I can recall those details
because of how she does it.
I'm always excited to learn from her
and I look forward to more presentations.
In closing, Dr. Keegan
approaches her research
and all other academic work
she's been involved with
with inquisitiveness, rigor, patience
and an attention to detail.
I am so happy to call her a
colleague and I congratulate her
on this accomplishment.
(audience clapping)
– Thank you, Dr. Ennis for those comments.
Next, it's my privilege to
introduce Dr. Sally Camper,
the Margery Shaw Distinguished University
Professor of Human Genetics
and Professor of Internal Medicine.
Dr. Camper, as we've heard
was Dr. Keegan's PhD advisor,
and has served as a mentor
throughout Dr. Keegan's
very illustrious career.
Dr. Keegan credits her PhD
research with Dr. Camper
as the point in her academic career
when she became interested in pediatrics
and the importance of
developmental processes
in having healthy babies.
Dr. Camper is unable
to join us live today,
but we will hear from her
now from prerecorded remarks,
she sent us so she could
acknowledge and celebrate
this very special occasion with us.
– Hi, I'm Sally Camper.
I'm really delighted to
have an opportunity today
to say a few words in
honor of Dr. Katie Keegan,
as she receives an Endowed
Professorship in Pediatrics.
One of the best things
about being a scientist
is mentoring trainees,
not just for the time you're together,
but also for the decades that follow
as you continue to watch with pride
as their careers flourish.
I'm really proud of
Katie's accomplishments
as a Physician Scientist and
the Pediatric Geneticists
that she has become with really
an international reputation.
I was a brand new Assistant
Professor in 1988,
when Katie joined my laboratory
for her PhD research.
She was bright, engaging
and asked all kinds
of great questions at lab meetings.
And I felt lucky to have her in the group.
She worked together with
another Assistant Professor
Audrey C Schultz and me
mapping out the elements
that are necessary to drive expression
of corticotropin-releasing hormone,
that hypothalamic hormone that regulates
the fight-or-flight response.
And that was using
genetically engineered mice
at a time when that
technology was very new
at University of Michigan
and it involved her wanting
a lot of neuroanatomy.
She was very productive in her research
and published five research articles.
As a student, she was also
very active in the MSTP program
and the Asylum Molecular
Biology Graduate Program.
And she was the one who
recruited other graduate students
to my lab, so I'm very grateful for that.
She was really effective
in mentoring undergraduates
and other graduate students as
they launched their careers.
These characteristics that
she displayed as a PhD student
have continued to manifest
throughout her career.
She's continued to vote herself
to high quality research,
carving out a great niche for herself
in Euro genital development
and disorders of sexual development.
And she has continued to
bridge her patient care
with discovery science,
using animal models.
She's continued to mentor
others and serve the institution
as an educator and medical
director for several
of our different educational programs,
including the MSTP
and the Genetic Counseling
Program in Human Genetics.
And on top of that,
she's well-regarded as
a Medical Geneticist,
which is a field that is berms in a way
that I don't think any of us
could have anticipated 30 years ago.
Katie is really an impressive
individual who epitomises
what we hope for in Physician Scientists
and the way she cares for children
communicates with their parents,
mentors and educates the
next generation of physicians
and scientists and discovers
new important information
about the causes of
developmental disorders.
Really proud of you, Katie.
And this is a well
deserved honor, thank you.
– So we're certainly
grateful for those comments
from Dr. Camper who could
not be with us live today,
but clearly those are
very heartfelt comments.
Like Mr. Lytle,
whose generosity made this
Professorship possible.
Dr. Katie or Catherine Keegan is committed
to creating a brighter future
for children with chronic
and debilitating medical conditions.
For more than 20 years,
she has dedicated her
career to finding answers
for families, seeking more knowledge,
improving counseling or accurate diagnoses
and better treatments for
the genetic conditions
or birth defects affecting their children.
As you heard, she's a proud
alum of our MSTP program,
earning both her MD and PhD degrees here.
Throughout her career,
Dr. Keegan has been able to
combine her research interests
with her love of working
with children in the clinic
and their families,
as well as clearly her
strong educational interests,
which really helps build
the future of physicians
and physician scientists
who in their own right
will make significant contributions.
We've heard a lot about her
research and suffice it to say,
it's groundbreaking, it's
continuing to transform the field.
And she continues to be an
internationally recognized leader
in the field of research, but
she's truly a triple threat
devoting time to high quality education,
leadership roles and high quality,
compassionate care of
patients and families.
In her laboratory and
throughout her clinical work,
Dr. Keegan has really guided a
number of students residence,
hall officers, fellows and
other learners and help them
to establish their own careers
and move on to other positions either here
or at other fine academic institutions,
where they too can make an
impact on patients, families,
and the future of medicine.
We are delighted that the inaugural holder
of the Lytle Professorship
is impacting the field of
Genetics and Pediatric Medicine
in so many ways.
Dr. Keegan, congratulations
on becoming the inaugural
Charles E. Lytle Junior Research
Professor in Pediatrics,
which we are marking by bestowing you
with this special medallion
on behalf of the regions
of the University of Michigan.
Thank you for your contributions
to Michigan Medicine,
our Medical School and our University.
And as we always like to
say at these celebrations,
as long as there is a
University of Michigan,
there will be a Charles
E. Lytle Junior Research
Professorship in
Pediatrics, congratulations.
– Thank you very much.
(audience clapping)
– I invite you to give
your inaugural address.
– Thank you.
Thanks everyone for being here in person
or tuning in virtually.
I appreciate having all of you be present
either here or virtually.
So I'm really honored to
have this professorship.
And, so I thought I
would spend my time today
just going through my career.
You've probably already
heard a lot of these pieces
of information, little
snippets from Donna and Jeff
and Dr. Bradford, but I'll sort of go
through my journey for you.
So everything started in
terms of my introduction
to research back when I
was an undergraduate here
at the University of Michigan,
and I decided to work in the lab
of Dr. David Ginsburg as an undergraduate.
And at that time he was
a new Assistant Professor
in the Department of Human
Genetics and Internal Medicine.
And I actually worked under the mentorship
of Mark Roth in his lab,
who was a young hematology oncology fellow
becoming a junior faculty
member at the time.
And working in David's lab
really ignited my passion
for working at the bench
and in this new field
at the time of Molecular Biology.
And one of the things that I learned
was how to do a Southern blot
and so this is actually in the very,
very early days of immunotherapy.
And what we were doing was studying
a mouse lymphoma cell line
and following treatment
with a monoclonal antibody.
There were several
subpopulations of this cell line
that would escape the treatment.
And what we found was over
here is that when we looked at
the mechanism of this
escape from treatment,
we found that these different subclones
or subpopulations were rearranging
their Kappa light chain genes
in order to escape the tumor therapy.
One of the other things
that in David's lab
was that he being a geneticist himself
taught me how to think like a geneticist,
which I've carried with me
and for my entire career.
And then I was lucky enough
to enroll in the MSTP here
and during graduate school
and the CMD program,
I worked in the lab of
obviously, as, you know,
Sally Camper and Audrey C
Schultz was my co-mentor.
And as Sally mentioned,
she also was a new assistant
professor at that time.
And what we studied was the stress hormone
corticotropin-releasing hormone.
And we were, as Sally said,
trying to understand the
elements that regulate the cells
specific expression of CRH.
And one of the things that
we did was we looked at
expression during the development,
and we found that Sirius
has actually expressed
in the fetal lung,
in addition to the
normal site of expression
that everybody is aware
of in the hypothalamus.
And so that was sort of a
really interesting finding.
During my time in Sally's lab,
really learned the power
of using the mouse model
to study mammalian development.
And I also learned from Sally and Audrey,
how to think like a
scientist and I benefited
from their wonderful mentorship
and have tried to emulate
a lot of the skills
that they used in their
mentorship with me.
Then after I finished my graduate work,
I was lucky enough to
do an elective rotation
in Pediatric Genetics with Dr. Ennis,
who I sort of knew from
working in the Human Genetics
Department and also Jane Sheward,
who was our Genetic
Counselor at that time.
And I felt really lucky
because they actually took me
to an outreach clinic in Trevor City.
And so I was able to see
patients in a beautiful spot,
and it really fostered my
passion for Medical Genetics
as a specialty.
And that really never changed
throughout the rest of
my medical training.
And then I decided move to Boston
to do my Pediatrics Residency.
And during that time,
I learned how to think like a pediatrician
and I made lifelong
friends and really enjoyed
living on the East Coast, near
the mountains in the ocean.
And one of the things that we
used to do in our, you know,
rare free weekends is we would go hiking
in the white mountains.
And that was a really
great time of our lives.
Then I came back to Michigan
to do my Medical Genetics Fellowship.
And as Jeff alluded to, I
was in a class with Donna
as a co-fellow and also Peter Haddara,
who is a neurologist who got
training in Medical Genetics
at the same time.
And during that period of time,
I learned how to think
like a Medical Geneticist
and received outstanding
training here in our program.
And then I had wonderful
colleagues that I have maintained
relationships with throughout my career.
So just to talk about this
is where I really developed
my clinical interests and
because of my background
in Developmental Biology, and
in understanding, you know,
mouse, developmental genetics,
I was really interested in
structural birth defects.
And these are serious birth defects
that occur in 6% of babies worldwide.
In the U.S, birth defects
are the leading cause
of infant death.
And they're responsible
for about one in five
infant deaths in the United States.
And the hospital costs associated
with treating birth defects
are over 2.4 billion per year.
And this is actually from a
study that's probably 10 years
old at this point, so
it's probably higher now.
There's also a significant
emotional toll on families
when they don't understand why their child
has a birth defect or what, you know,
what happened to cause this.
And really during my fellowship,
there was a very limited understanding
of the genetic etiologies
of these birth defects.
And then also based on my
interest in endocrine disorders
from Sally's lab,
I became interested in
endocrine genetic disorders,
as well as disorders of sex development,
which I have continued to be interested
in these clinical
conditions during my career.
And at that time, when I
finished my fellowship,
we had only a small number
of tools available to us
to make a diagnosis.
We had a karyotype or the
routine chromosome analysis,
and then we were able to do
fluorescence in situ hybridization
and gene sequencing for a very
small number of conditions.
And since then, you know,
the possibilities in terms
of the tools available to us
have increased exponentially.
So then I started my
transition to faculty position
and Valerie Opipari was becoming chair
of the Department of
Pediatrics at that time.
And she was incredibly supportive of me
as I started my career
as a faculty member,
and also through many
years following that.
And because of my interest
in endocrine disorders,
I worked in the lab of Gary Hammer
and the Department of Internal Medicine.
And actually he was also a
young assistant professor
at the time.
And we'd decided to study
this mouse model here.
This mouse called the ACD master,
the adrenal cortical dysplasia mouse.
And we were interested in this mouse model
because it had abnormal
adrenal gland development here,
and also infertility shown by
abnormal seminiferous tubules
in the testes.
And our goal was to identify the gene
that caused the ACD mouse mutation.
And we did identify it, but
we were surprised to see
that it was a mutation in a
gene that encodes this protein
called TPP1, which is
a protein that's part
of the shelter and complex
that's important for telomere maintenance.
And so it protects the
ends of the telomeres,
which are these little
bright spots at the end
of the blue chromosomes.
And it was really fascinating
to us that this mutation
in a gene that is expressed in every cell
in the body could cause
such a specific phenotype.
And so I went on to study
this gene in development,
and we wanted to understand
the phenotype of the ACD
mutation during development.
And we were fascinated to
see that the ACD mouse mutant
had this sort of coddle truncation
or abnormal caudal development.
So the lower half of the mouse embryo
did not develop correctly.
And one of the first things
we wanted to do in the lab
is try to understand why that occurred.
And so given that the gene
was involved in telomere maintenance,
we thought maybe this was a
result of genome instability.
And so we found that in our mouse mutant,
there was an increase in Apoptosis
shown by caspase-3 staining.
And then when we crossed
the p53 deficiencies,
p53 deficient mice,
we were able to rescue
this phenotype shown here.
So during this time there were
a lot of labs studying TPP1
and sheltering and the telomere complex,
and people started to understand
that there were domain
specific functions of ACD or TPP1.
And so on the N-terminus is the OB-fold,
that's important for
recruitment of telomerase
and for telomerase function.
And then in the middle, is
the POT1 binding domain,
which binds to this protein POT1,
which is a single
stranded binding protein,
at the telomere and TPP1 and POT1,
form a heterodimer at the telomere.
And then at the C-terminus,
there's the ten-2 binding domain,
which binds to this protein ten-2,
and tethers the rest of the
complex to the other double
stranded binding proteins here.
And so as people identify
these different functions
of these domains, the
role of TPP1 in protecting
and maintaining telomeres
was further characterized.
And then meanwhile, other
groups were studying a disease
called Dyskeratosis congenital.
And this was an inherited
bone marrow failure syndrome,
which is characterized
by bone marrow failure
and then very short telomeres.
And individuals with this
condition have other features
and the classic triad that's associated
with Dyskeratosis congenital
is there's nail dystrophy
and then oral leukoplakia,
there's white plaques on the tongue
and then abnormal
pigmentation of the skin.
And there are also another
other medical problems
that these patients can have,
including pulmonary fibrosis,
cerebellar hypoplasia
and they also have a high risk of cancer.
And the people who were
studying this condition
recognize that it was
due to short telomeres
causing STEM cell dysfunction.
And several groups found that
pathogenic variants in genes
that were important for telomere function
were the cause of Dyskeratosis congenital.
So genes like telomerase
and other proteins
that interact with telomerase
and help it function.
And so that sort of led
to a long and productive
collaboration with first Yvonne Maynard
who was at the University of Michigan
and has since moved to
University of Pennsylvania.
And we wanted to study the
effect of ACD gene deletion,
or lack of TPP1 or ACD
function in the bone marrow.
And we showed that when
we deleted that gene
from mouse cells, the
hematopoietic STEM cells
were lost or disappeared.
And then a little bit
following that Sharon Savage,
a friend of mine at the NIH,
a friend and collaborator was
studying this family up here
with where there was a child
who developed a bone marrow
failure at a very early age
and had extremely short telomeres.
And so he was diagnosed
with a rare variant
of Dyskeratosis congenital
and it was also found that
his sister and his father
had extremely short telomeres as well.
And so that led to the suspicion
that there could be an
underlying genetic cause.
And so Sharon and at this
time was when exome sequencing
was first coming out and
she performed sequencing
on this family and found
that there was a variance
in the ACD, TPP1 gene in this child
that was inherited from his father.
And so we like to call this
variant the K1-70 Delta,
because it's a deletion
of the lysine residue
at the amino acid position 170.
And so that variant was right
in this region of the protein
called the TEL patch.
And the TEL patch had been
characterized by JK Nandakumar
during his postdoctoral
work with Tom Chek.
And JK was just moving to
University of Michigan,
lucky for me and we
started a collaboration
to understand whether or not this variant
was functionally
significant in this family.
And we did show that in
cells, from this patient,
there was a defect in recruiting
telomerase to telomeres,
and also in telomerase function.
And so it caused a secondary
telomerase deficiency
in this family.
And then as an aside,
Sharon had also found
this other variant P491T,
which this child had
inherited from his mother,
which was in the tin binding domain.
And we initially thought that that variant
might also be having an
effect on the ability of TPP1
to bind to ten-2 and later
on with additional studies,
we found that that variant did
not seem to have an effect.
So it's really just the
K1-70 Delta variant.
And so I'm working with Yvonne and JK.
Our next project was to
model this K1-70 Delta
mutation in the mouse.
And we weren't quite sure
what the phenotype would be,
but we thought it would be
milder than when we just deleted
the entire ACD gene and
found that the absence
of hematopoietic STEM
cells and in the mouse,
what we found was there was
really no effect or very small,
minor effects on the bone marrow,
but there's actually a striking
infertility that occurs
after four generations, which
is different from humans.
Where in that human family,
there was bone marrow failure,
but not really any
evidence of infertility.
And so one of the things
that we're working on now
is to try to understand why
those mice have infertility
and what's the effect of this
mutation on telomere function
in the germ cells and
this is just showing,
I just wanted to show
this beautiful staining
done by Jackie Granule,
a grad student working
in JK's lab showing
staining of the spermatids
in the blue here.
And then there's a spermatagonia marker
and a spermatocyte marker.
And these are just from wild type mice,
but we're gonna use the staining
for these different types of cells
and compare the wild type
mice and the mutant mice.
And these studies are ongoing right now.
And then, you know, I
really was interested in,
in telomere disfunction,
but I wanted to get back
to studying birth defects
of the caudal region,
which is kind of how I started my career.
Now, these birth defects are
really not that uncommon.
It's estimated that their incidence
is about one in 7,500 births,
and there are a range of birth defects,
including neural tube defects
or spina bifida imperforate anus.
There are also clinical malformations,
which affect the gastrointestinal
and genital urinary systems,
and then caudal regression,
which affects the spine,
the gastrointestinal and
the genital urinary systems.
And then there's also something
called factoral association,
which is familiar to us in genetics,
which can include other defects,
such as cardiac defects and
tracheoesophageal fistula.
And even today with all the
advances in genetic testing
and technology and new genes,
we really know very little
about the underlying genetic
etiology of these conditions.
We do know that there are some genetic
and environmental factors,
and it's known that maternal diabetes
particularly poorly
controlled maternal diabetes
is a very high risk factor
for caudal regression,
but nobody understands how that occurs.
So this sort of led me to
study another mouse model
called the Danforth's
Short Tail Mouse Model
or Sd for short.
And these studies were
spearheaded by Chris Vlangos,
who was a postdoc in my lab.
And you can see that the
Danforth's Short Tail Mouse
has sort of a shortened
back end with a short tail.
And we had an idea of where
the mutation was located
because it had been
mapped to a specific area
on chromosome 2.
And so we sequenced that entire region
using next generation
sequencing technology.
And we found that the mutation
was due to a retrotransposon
insertion, which didn't interrupt a gene,
but an inserted between
several different genes
in this region.
And when we were looking at
which gene might be responsible,
we noticed that there's this gene
called PTF1A or pancreas
specific transcription factor.
And what happened was when
the retrotransposon inserted
into this region, there
must be enhancer elements
in that retrotransposon sequence.
And it caused ectopic or
abnormal expression of PTF1A
in the developing embryo.
So in a wild type embryo,
there's really no expression at all,
of PTF1A and the tail bud,
whereas in the mutant embryo,
there's a very high level of expression,
and it probably disrupts
the developmental regulatory
programs that are important
for cuddle development.
And so these studies led
to another great productive
collaboration with Steve Parker
and the Department of
Computational Medicine
and Bioinformatics.
And Steve and I worked together on was
to look at both the transcriptome
and the chromatin
accessibility in the SD mutant
versus the wild type embryo.
So this is our transcriptome studies,
and these are ATAC-seq
or the chromatin accessibility studies.
And we took little tiny bits
of the tail bud of the mouse
embryos of the wild
type versus our mutant.
And we were able to show that
indeed there was upregulation
of PTF1A as you can see
here in the mutant embryo
versus the wild type embryo
where it's not expressed at all.
And then we also found that
there was a significant peak
of increased chromatin
accessibility, just upstream,
of PTF1A, a near this long non-coding RNA.
And when we compared those
sequences to the human genome,
we found that this region
corresponded to a human region,
which contained an enhancer of PTF1A.
Another study that we did was to look at
differential gene expression
between the mutant embryos
and the wild type embryos here.
And we found that a number of genes
were either upregulated or downregulated.
And when we looked more
specifically at those genes
and what their functions
were by a pathway analysis,
we found that looking at
several different developmental
regulatory pathways, we found
that the hedgehog pathway
was actually dysregulated
in the mutant embryos.
And we confirm that by looking at embryos,
looking at Sonic hedgehog expression
and showing that Sonic hedgehog expression
was absent from the tail,
but of the mutant embryos,
as well as this other gene and kx2.9,
which is also reduced
and that's regulated by Sonic hedgehog.
So that was really interesting to us.
And now we're working
on additional studies
that we are doing called multiomics.
So to do these studies,
we're integrating multiple sets of data,
including chromatin and
transcriptome studies
and single cells.
And, what we would like to
do is identify enhancers
and other noncoding elements in the mouse
during cuddle development.
And then we plan to map these
elements to the human genome,
and then look for variations
in these conserved elements
that might explain some
human caudal birth defects,
and we're working on an R1
that's due at the end of this month.
So finally, I just like to
acknowledge people in my lab
who contributed to these projects,
Janna Hutz, Bridget O'Connor,
who's now a Genetic Counselor
in Pediatric Genetics,
and Erica Macke worked
on the initial ACD mouse
studies last year and Ceren
Sucularli was a postdoc
who worked on the ACD project.
Hande Kocak was a graduate
student who worked
on the family with this
Dyskeratosis congenital,
James White and Peter Kale Thomas
worked on the Danforth's project
and Jackie Graniella is currently
working on the mouse studies
with the infertility phenotype.
And then there's a list
of a lot of other people
who've worked in my lab
during this time period.
And then I'd just like
to acknowledge and thank,
Donna and Jeff, who had
been a wonderful friends,
colleagues and mentors
throughout all these years.
And it's been such a pleasure
working with them every day.
And I really appreciate all of the support
that they've given me over the years.
I'd also like to thank my
colleagues in Pediatric Genetics
and Human Genetics and my funding sources,
including NIH, NICHD, March of Dimes
and American Cancer Society.
And I'm also very grateful and thankful
for Charles E. Lytle Junior and his family
for donating this money that
will support my research.
And then finally, I'd
like to thank my family.
This is a picture of my
entire extended family
at a family reunion event last year.
And then my parents who
this is a picture of my dad
at his 90th birthday a year ago.
So he's oh, 91 this year.
And my mom is turning
91 and just a few weeks.
And they are both doing very well.
And then finally my
close family, my husband,
Mike of 29 years,
who has been with me
throughout my careers,
even dating back to the days when I worked
in David Ginsburg's lab.
And then my daughter,
Carly who's 20 and a
rising senior at Michigan,
well, not a rising senior,
she is a senior at
Michigan State university
and my son, Michael, who
is a senior at Greenhills.
And I'm really thankful
that they provided me
so much support and don't
make fun of me too often.
And I think that's it.
(audience clapping)
– So congratulations, Dr. Keagan,
what a remarkable career you have had,
and we know that you will
continue to make meaningful
and important contributions
across the tripartite mission.
You got your undergraduate degree here
in Cell and Molecular Biology as well.
That's also my undergraduate degree.
And I also share with you three degrees
from the University of
Michigan, so congratulations.
Education clearly makes a huge difference.
And again, congratulations
on your lovely family
who are celebrating with us today.
So thank you to all of the speakers
and to everybody who is joining
us virtually this evening
in these clearly unusual times,
but we are definitely
making the best of it.
I also wanted to send a special
thank you to development
and our events team who makes
these amazing events happen.
Thank you, Don.
Thank you, Dr. Keegan,
and on becoming the first Charles E. Lytle
Research Professor in Pediatrics.
Thank you and have a good evening.
Please stay safe.

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