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Kathleen J. Millen, PhD

Children's Title: Principal Investigator

Academic Title: Associate Professor

Research Center: Center for Integrative Brain Research

"As an undergraduate student, I fell in love with developmental biology while watching a fertilized worm egg divide and turn into a complex embryo in real time, under a microscope. From that day forward, I’ve marveled at the complex symphony of biological events that create each one of us. Studying brain birth defects provides me with the ability to study the basic mechanisms of developmental biology while also having an impact on the clinical care of affected individuals and their families."

Kathleen J. Millen, PhD, is associate professor of pediatrics at the University of Washington School of Medicine. She is also a Principal Investigator at the Seattle Children’s Hospital Research Institute, Center for Integrative Brain Research. Her research laboratory focuses on the genetic basis of early brain development mental retardation, autism and hydrocephalus.

In particular, her lab uses the synergy of both human and mouse genetics to identify genes causing cerebellar malformations and then defines the underlying developmental processes necessary for normal development. Although her studies are of basic science interest, they also have considerable clinical relevance. Specifically, her group identified the first genes for human Dandy-Walker malformation, the most common structural defect of the cerebellum affecting 1/5000 births and often causing significant intellectual and motor delays. Concurrently she is also studying multiple mouse mutants with abnormal cerebellar development to gain insights into the fundamental developmental programs that drive brain cell fate specification and patterning. These studies in turn provide new candidate genes for human developmental brain disorders.

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Significant Recruits of 2010

2010 was a banner year for recruiting at Seattle Children’s Research Institute as several nationally recognized researchers chose to continue their life’s work in Seattle.... cont.

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Overview
Awards and Honors
Publications
Research Funding

Overview

Medical/Professional School: University of Toronto, Toronto
Fellowship: The Rockefeller University, New York
Research Description: Our research program seeks to explore the molecular genetic pathways and cellular processes which determine how the developing vertebrate Central Nervous System (CNS) acquires pattern during early neurogenesis. We primarily focus on congenital malformations of the cerebellum and has implications for the genetic basis of mental retardation and autism. Our approach is to combine the power and strengths of both mouse and human genetics with embryological analysis in mice and other model vertebrates, to identify the molecular and cellular events that regulate cerebellar development.

We have identified the first genes for Dandy-Walker malformation, the most common structural defect of the cerebellum affecting 1/5000 births and causing significant intellectual and motor delays. Using mice to model these defects we have defined the developmental basis of the pathology and gained new insights regarding novel mechanisms of CNS development. Concurrenlty we are studying multiple mouse mutants with abnormal cerebellar development to gain insights into the fundamental developmental programs that drive cerebellar cell fate specification and patterning.
Lab URL: http://depts.washington.edu/millenwb/home/
Research Focus Area: Stem Cell Biology, Neuroscience / Neurodevelopment, Genetics and Developmental Biology

Awards and Honors

Award Name	Award Description	Awarded By	Award Date
	This project investigates cardiac energetics during development and during cardiopulmonary bypass in an animal model in vivo. The study employs cardiopulmonary bypass techniques 31Phosporous, and 13Carbon NMR.
	This project is aimed at studying Secreted Proteins from Endothelial cells for Endocrine Development (SPEED). The major goal of our sub-project is to perform high-throughput proteomics analysis of endothelial cells.

Publications

Consensus Paper: Pathological Role of the Cerebellum in Autism.
Cerebellum (London, England) , 2012 Feb 28

Wormless without wingless.
Nature medicine , 2011 Jun: 17(6)663-5

Zac1 plays a key role in the development of specific neuronal subsets in the mouse cerebellum.
Neural development , 2011 May 18: 625

Multiple developmental programs are altered by loss of Zic1 and Zic4 to cause Dandy-Walker malformation cerebellar pathogenesis.
Development (Cambridge, England) , 2011 Mar: 138(6)1207-16

Cerebellar hypoplasia and Cohen syndrome: a confirmed association.
American journal of medical genetics. Part A , 2010 Sep: 152A(9)2390-3

Phenotypic and genetic analysis of the cerebellar mutant tmgc26, a new ENU-induced ROR-alpha allele.
The European journal of neuroscience , 2010 Aug 16

Lmx1a regulates fates and location of cells originating from the cerebellar rhombic lip and telencephalic cortical hem.
Proceedings of the National Academy of Sciences of the United States of America , 2010 Jun 8: 10725-30

Novel Approaches to Studying the Genetic Basis of Cerebellar Development.
Cerebellum (London, England) , 2010 Apr 13

A developmental and genetic classification for midbrain-hindbrain malformations.
Brain : a journal of neurology , 2009 Dec: 3199-230

Looking at cerebellar malformations through text-mined interactomes of mice and humans.
PLoS computational biology , 2009 Nov: e1000559

Overlapping function of Lmx1a and Lmx1b in anterior hindbrain roof plate formation and cerebellar growth.
The Journal of neuroscience : the official journal of the Society for Neuroscience , 2009 Sep 9: 11377-84

Lmx1a maintains proper neurogenic, sensory, and non-sensory domains in the mammalian inner ear.
Developmental biology , 2009 Sep 1: 14-25

FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation.
Nature genetics , 2009 Sep: 1037-42

Model organisms inform the search for the genes and developmental pathology underlying malformations of the human hindbrain.
Seminars in pediatric neurology , 2009 Sep: 155-63

Genetic variation and population substructure in outbred CD-1 mice: implications for genome-wide association studies.
PloS one , 2009: e4729

Lmx1a is required for segregation of sensory epithelia and normal ear histogenesis and morphogenesis.
Cell and tissue research , 2008 Dec: 339-58

Linkage to chromosome 2q36.1 in autosomal dominant Dandy-Walker malformation with occipital cephalocele and evidence for genetic heterogeneity.
Human genetics , 2008 Apr: 237-45

Zic1 and Zic4 regulate zebrafish roof plate specification and hindbrain ventricle morphogenesis.
Developmental biology , 2008 Feb 15: 376-92

Cerebellar development and disease.
Current opinion in neurobiology , 2008 Feb: 12-9

Proprioceptive sensory neuropathy in mice with a mutation in the cytoplasmic Dynein heavy chain 1 gene.
The Journal of neuroscience : the official journal of the Society for Neuroscience , 2007 Dec 26: 14515-24

A developmental classification of malformations of the brainstem.
Annals of neurology , 2007 Dec: 625-39

Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool.
The Journal of neuroscience : the official journal of the Society for Neuroscience , 2007 Sep 5: 9780-9

Mapping of deletion and translocation breakpoints in 1q44 implicates the serine/threonine kinase AKT3 in postnatal microcephaly and agenesis of the corpus callosum.
American journal of human genetics , 2007 Aug: 292-303

Understanding cerebellar pattern formation.
Journal of visualized experiments : JoVE , 2007: 407

In ovo electroporations of HH stage 10 chicken embryos.
Journal of visualized experiments : JoVE , 2007: 408

Molecular definition of an allelic series of mutations disrupting the mouse Lmx1a (dreher) gene.
Mammalian genome : official journal of the International Mammalian Genome Society , 2006 Oct: 1025-32

The roof plate regulates cerebellar cell-type specification and proliferation.
Development (Cambridge, England) , 2006 Aug: 2793-804

Roof plate-dependent patterning of the vertebrate dorsal central nervous system.
Developmental biology , 2005 Jan 15: 287-95

Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation.
Nature genetics , 2004 Oct: 1053-5

Mechanisms of roof plate formation in the vertebrate CNS.
Nature reviews. Neuroscience , 2004 Oct: 808-12

Control of roof plate development and signaling by Lmx1b in the caudal vertebrate CNS.
The Journal of neuroscience : the official journal of the Society for Neuroscience , 2004 Jun 23: 5694-703

Control of roof plate formation by Lmx1a in the developing spinal cord.
Development (Cambridge, England) , 2004 Jun: 2693-705

Development and malformations of the cerebellum in mice.
Molecular genetics and metabolism , 2003 Sep-Oct: 54-65

Reciprocal fusion transcripts of two novel Zn-finger genes in a female with absence of the corpus callosum, ocular colobomas and a balanced translocation between chromosomes 2p24 and 9q32.
European journal of human genetics : EJHG , 2003 Jul: 527-34

Research Funding

Grant Title	Grantor	Award Date
"Dorsal midline patterning in the vertebrate CNS"	NIH (NINDS)	Sept. 1, 2010 - Aug. 30, 1915
Rapid and inexpensive screening of disease candidate genes in mice	NIH (DO)	Sept. 30, 2009 - Sept. 29, 2011
Tippy a novel mouse model for human ataxia and epilepsy	NIH (NINDS)	June 1, 2009 - May 31, 2011
The Genetic Link Between Autism and Structural Cerebellar Malformations	Autism Speaks	Jan. 1, 2009
Role of ZIC and GLI protein-protein interactions in human brain disorders	NIH NICHHD	July 1, 2008
CA14599	NIH	April 1, 2008
Contribution of 22q13 Deletion to Cerebellar Malformation	22q13 Deletion Foundation	March 1, 2008
De novo copy number variation and gene discovery in human brain malformations	NIH	March 1, 2008
Mouse Models of 6p25 Dandy-Walker Malformations	March of Dimes	June 1, 2007
Autism Speaks-Mentor based pre-doctoral fellowship	Autism Speaks	Feb. 1, 2007
J.P. Kennedy Intellectual Delay and Developmental Disabilities Center	NIH	Sept. 15, 2006
The Genetic Basis of Mid-Hindbrain Malformations	NIH	Sept. 15, 2005
Mouse Models of Human Cerebellar Malformations	NIH	Sept. 15, 2004
Roles of Zic Genes in Vertebrate Hindbrain Development	NIH (NINDS)	Sept. 5, 2004
Genetic Analysis of Roof Plate Function in the CNS	NIH	July 1, 2004

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Seattle, WA 98101

206-884-3225

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Kathleen J. Millen, PhD

Making a Difference

Significant Recruits of 2010

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Overview

Awards and Honors

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