Chen-Ming Fan

Staff Member

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Office (410) 246-3022
Lab (410) 246-3039
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Nathalie Gerassimov

Yun Bai

Anwen Shao

Jiaxiang Tao

Undergraduate Students

Colt Crain

Visiting Scholars

Harry Goldberg

RESEARCH INTERESTS

My laboratory studies the molecular mechanisms that govern mammalian development, using the mouse as a model. We use a combination of biochemical, molecular and genetic approaches to identify and characterize signaling molecules and pathways that control the development and maintenance of the musculoskeletal and hypothalamic systems.

The muskuloskeletal system:

The musculoskeletal system provides the mechanical support for our posture and movement. How it arises during embryogenesis pertains to the basic problem of embryonic induction. How the components of this system are repaired after injury and maintained throughout life is of biological and clinical significance. We study how this system is generated and maintained.

The origin and induction: The musculoskeletal system of the trunk originates from a common embryonic structure called the somite. Somites are segmented mesodermal units flanking both sides of the spinal cord. Their reiterated pattern is the basis for the repeated organization of the trunk. Under the inductive influence of adjacent tissues, cells within the somite give rise to muscles and bones. We have developed a 3-dimensional culture system that allows characterization of crucial long-range and contact-dependent cellular interactions that induce early skeletal and muscle fates. Our efforts toward designing new methods and assays to track somite development have enabled us to make novel observations.

Induction of the axial skeletal progenitors: We have identified the Hedgehog (Hh) proteins responsible for inducing the early skeletal fate. Hh largely utilizes evolutionarily conserved downstream mediators for inductive signaling. In addition, we also found a vertebrate-specific cell surface Hh binding protein Gas1. Gas1 mutants display skeletal defects related to or due to altered Hh signaling. Mechanistically, Gas1 helps transform the Hh diffusion gradient into its observed signaling activity gradient. This unexpected mechanism provides a new vision of Hh signaling pathway initiation and has direct implications for the long-range action of Hh.

Induction of the early embryonic muscle: Conversely, the Wnt family of proteins plays a key role in inducing the dermis/muscle dual potential progenitors. Combining our in vitro assay with microarrays analyses, we have uncovered previously unknown effectors and target genes of Wnt. Using an ex vivo whole embryo culture system coupled with somite-specific gene delivery, we discovered an unconventional pathway for Wnt signaling via the adenylyl cyclase/protein kinase A/Creb cascade that selectively activates myogenic transcriptional determinants Myf5 and MyoD.

Embryonic and adult muscle stem cells: Somites not only supply cells for embryonic muscles, but also contain muscle progenitors. The proliferative capacity of these progenitors depends upon the transcription factors Pax3 and Pax7. Both genes are activated by Wnt. Using inducible cell lineage tracing, we have found that early Pax7-expressing somitic cells directly give rise to adult muscle stem cells, i.e. the satellite cells. Lineage tracing of Pax7-expressing adult satellite cells indicates that they are indeed a stem cell source for muscle regeneration. Conditional inactivation of Pax7 at different developmental time points reveals that Pax7 is required for the proliferative properties of muscle progenitors up to 3 weeks after birth when they transition into quiescence. After this transition is made, however, both Pax3 and Pax7 are completely dispensable. Our finding of an age-dependent cell-intrinsic change in the genetic requirement for muscle stem cells cautions against inferring adult stem cell biology from embryonic studies, and has direct implications for the use of stem cells from hosts of different ages in transplantation-based therapies.

The neuroendocrine hypothalamus:

The hypothalamus is an essential brain center that maintains multiple physiological homeostatic processes by modulating pituitary hormone secretions. Two centers (nuclei) of the hypothalamus, the paraventricular and supraoptic nuclei (PVN and SON), contain various hormone-producing neurons. Studies of these hormones have been instrumental to our understanding of endocrine homeostasis, including the maintenance of bodily fluid osmolarity and the balance of energy metabolism. Despite the importance of PVN and SON function, molecules that control their embryonic specification, neuronal differentiation, nucleus formation, and neuronal connections are largely unknown.

During early embryogenesis, the PVN and SON have a common origin but segregate from each other to diversify their inputs from other brain regions. After their segregation, the PVN and SON project axons to other homeostasis centers, including the pituitary. Through a series of genetic analyses, we have constructed a hierarchical map composed of five transcription factors that define the key steps of proliferation, survival, differentiation, and hormone expression of the PVN and SON neurons during development. Sitting at the top of this genetic cascade is the Sim1 gene, which also controls both the segregation and axonal projections of the PVN and SON. We have therefore expanded our work to investigate neuronal migration cues. We found that a Sim1 downstream gene, PlexinC1 (a receptor for neuronal guidance signals), mediates PVN and SON segregation.

We found that heterozygosity at the Sim1 locus causes the animal to develop morbid obesity due to over-feeding. Sim1 heterozygous mice exhibit compromised PVN structure and function, supporting a role for PVN in maintaining energy homeostasis via the regulation of feeding. Interestingly, people haploid for the SIM1 gene also clinically present with childhood obesity. Thus, our approach directed toward studying embryonic development of the PVN and SON has directly led us to identify a genetic contributor to feeding regulation and obesity in rodents and humans. Therefore, our basic developmental studies of the PVN and SON suggest a new avenue for finding genetic determinants of homeostasis regulation.

TITLE	YEAR
A microfluidic cell-migration assay for the prediction of progression-free survival and recurrence time of patients with glioblastoma BS Wong, SR Shah, CL Yankaskas, VK Bajpai, PH Wu, D Chin, ... Nature Biomedical Engineering, 1-15	2020
A Tppp3+ pdgfra+ tendon stem cell population contributes to regeneration and reveals a shared role for PDGF signalling in regeneration and fibrosis T Harvey, S Flamenco, CM Fan Nature cell biology 21 (12), 1490-1503	2019
Muscle stem cell renewal suppressed by GAS1 can be reversed by GDNF in mice L Li, M Rozo, S Yue, X Zheng, FJ Tan, C Lepper, CM Fan Nature metabolism 1 (10), 985-995	2019
Effects of Aging on the Viscoelastic Properties of Tissues and Cancer Cell Behavior S Park, J Tao, L Sun, CM Fan, Y Chen Biophysical Journal 116 (3), 296a	2019
An Economic, Modular, and Portable Skin Viscoelasticity Measurement Device for In Situ Longitudinal Studies S Park, J Tao, L Sun, CM Fan, Y Chen Molecules 24 (5), 907	2019
Origin of tendon stem cells in situ T Harvey, CM Fan Frontiers in Biology 13 (4), 263-276	2018
A CREB-MPP7-AMOT regulatory axis controls muscle stem cell expansion and self-renewal competence L Li, CM Fan Cell reports 21 (5), 1253-1266	2017
Interleukins 4 and 13 Induce Exon Skipping of Mutant Dystrophin Pre-mRNA to Restore Dystrophin Production SH Low, CM Fan bioRxiv, 207480	2017
Quantitative 3D Time Lapse Imaging of Muscle Progenitors in Skeletal Muscle of Live Mice MT Webster, T Harvey, CM Fan Bio-protocol 6 (24)	2016
Genetic interactions between the hedgehog co-receptors Gas1 and Boc regulate cell proliferation during murine palatogenesis GM Xavier, M Seppala, SN Papageorgiou, CM Fan, MT Cobourne Oncotarget 7 (48), 79233	2016
Targeting β1-integrin signaling enhances regeneration in aged and dystrophic muscle in mice M Rozo, L Li, CM Fan Nature medicine 22 (8), 889-896	2016
Loss of fibronectin from the aged stem cell niche affects the regenerative capacity of skeletal muscle in mice L Lukjanenko, MJ Jung, N Hegde, C Perruisseau-Carrier, E Migliavacca, ... Nature medicine 22 (8), 897-905	2016
Intravital imaging reveals ghost fibers as architectural units guiding myogenic progenitors during regeneration MT Webster, U Manor, J Lippincott-Schwartz, CM Fan Cell stem cell 18 (2), 243-252	2016
Growth arrest specific-1 (GAS1) is a C/EBP target gene that functions in ovulation and corpus luteum formation in mice YA Ren, Z Liu, LK Mullany, CM Fan, JAS Richards Biology of reproduction 94 (2), 44, 1-12	2016
WT1 targets Gas1 to maintain nephron progenitor cells by modulating FGF signals M Kann, E Bae, MO Lenz, L Li, BT Trannguyen, VA Schumacher, ... Development 142 (7), 1254-1266	2015
Acute tissue injury activates satellite cells and promotes sarcoma formation via the HGF/c-MET signaling pathway D Van Mater, L Añó, JM Blum, MT Webster, WQ Huang, N Williams, Y Ma, ... Cancer research 75 (3), 605-614	2015
Gas1 is a receptor for sonic hedgehog to repel enteric axons S Jin, DC Martinelli, X Zheng, M Tessier-Lavigne, CM Fan Proceedings of the National Academy of Sciences 112 (1), E73-E80	2015
HDAC 4 promotes P ax7‐dependent satellite cell activation and muscle regeneration MC Choi, S Ryu, R Hao, B Wang, M Kapur, CM Fan, TP Yao EMBO reports 15 (11), 1175-1183	2014
Boc modifies the spectrum of holoprosencephaly in the absence of Gas1 function M Seppala, GM Xavier, CM Fan, MT Cobourne Biology open 3 (8), 728-740	2014
A series of Cre‐ER^T2 drivers for manipulation of the skeletal muscle lineage S Southard, SH Low, L Li, M Rozo, T Harvey, CM Fan, C Lepper genesis 52 (8), 759-770	2014
The buccohypophyseal canal is an ancestral vertebrate trait maintained by modulation in sonic hedgehog signaling RH Khonsari, M Seppala, A Pradel, H Dutel, G Clement, O Lebedev, ... BMC biology 11 (1), 27	2013
Distinct and overlapping sarcoma subtypes initiated from muscle stem and progenitor cells JM Blum, L Añó, Z Li, D Van Mater, BD Bennett, M Sachdeva, I Lagutina, ... Cell reports 5 (4), 933-940	2013
c-MET regulates myoblast motility and myocyte fusion during adult skeletal muscle regeneration MT Webster, CM Fan PloS one 8 (11), e81757	2013
Myf5-Positive Satellite Cells Contribute to Pax7-Dependent Long-Term Maintenance of Adult Muscle Stem Cells S Günther, J Kim, S Kostin, C Lepper, CM Fan, T Braun Cell stem cell 13 (5), 590-601	2013
Oesophageal and sternohyal muscle fibres are novel Pax3-dependent migratory somite derivatives essential for ingestion JEN Minchin, VC Williams, Y Hinits, SH Low, P Tandon, CM Fan, ... Development 140 (14), 2972-2984	2013
Dynamic CREB family activity drives segmentation and posterior polarity specification in mammalian somitogenesis TP Lopez, CM Fan Proceedings of the National Academy of Sciences 110 (22), E2019-E2027	2013
Gastrointestinal defects of the Gas1 mutant involve dysregulated Hedgehog and Ret signaling S Biau, S Jin, CM Fan Biology open 2 (2), 144-155	2013
Role of satellite cells versus myofibers in muscle hypertrophy induced by inhibition of the myostatin/activin signaling pathway SJ Lee, TV Huynh, YS Lee, SM Sebald, SA Wilcox-Adelman, N Iwamori, ... Proceedings of the National Academy of Sciences 109 (35), E2353-E2360	2012
A transgenic Tbx6;CreER^T2 line for inducible gene manipulation in the presomitic mesoderm T Peter Lopez, CM Fan genesis 50 (6), 490-495	2012
Making skeletal muscle from progenitor and stem cells: development versus regeneration CM Fan, L Li, ME Rozo, C Lepper Wiley Interdisciplinary Reviews: Developmental Biology 1 (3), 315-327	2012
Missense substitutions in the GAS1 protein present in holoprosencephaly patients reduce the affinity for its ligand, SHH DE Pineda-Alvarez, E Roessler, P Hu, K Srivastava, BD Solomon, ... Human genetics 131 (2), 301-310	2012
Generating tamoxifen-inducible Cre alleles to investigate myogenesis in mice C Lepper, CM Fan Myogenesis, 297-308	2012
Mouse B-type lamins are required for proper organogenesis but not by embryonic stem cells Y Kim, AA Sharov, K McDole, M Cheng, H Hao, CM Fan, N Gaiano, ... Science 334 (6063), 1706-1710	2011
An absolute requirement for Pax7-positive satellite cells in acute injury-induced skeletal muscle regeneration C Lepper, TA Partridge, CM Fan Development 138 (17), 3639-3646	2011
Sim1 is a novel regulator in the differentiation of mouse dorsal raphe serotonergic neurons N Osterberg, M Wiehle, O Oehlke, S Heidrich, C Xu, CM Fan, K Krieglstein, ... PloS one 6 (4), e19239	2011
B-type lamins regulates neither their bound genes nor embryonic stem cells but are essential for organogenesis Y Kim, A Sharov, K Mcdole, M Cheng, H Hao, CM Fan, N Gaiano, M Ko, ... MOLECULAR BIOLOGY OF THE CELL 22	2011
Inducible lineage tracing of Pax7‐descendant cells reveals embryonic origin of adult satellite cells C Lepper, CM Fan genesis 48 (7), 424-436	2010
A role for borg5 during trophectoderm differentiation QP Vong, Z Liu, JG Yoo, R Chen, W Xie, AA Sharov, CM Fan, C Liu, ... Stem cells 28 (6), 1030-1038	2010
Counterfeiting the family jewels A Spradling, CM Fan Cell stem cell 6 (5), 405-406	2010
A sonic hedgehog missense mutation associated with holoprosencephaly causes defective binding to GAS1 DC Martinelli, CM Fan Journal of Biological Chemistry 284 (29), 19169-19172	2009
Adult satellite cells and embryonic muscle progenitors have distinct genetic requirements C Lepper, SJ Conway, CM Fan Nature 460 (7255), 627-631	2009
Primary cilia regulate Shh activity in the control of molar tooth number A Ohazama, CJ Haycraft, M Seppala, J Blackburn, S Ghafoor, ... Development 136 (6), 897-903	2009
V3 spinal neurons establish a robust and balanced locomotor rhythm during walking Y Zhang, S Narayan, E Geiman, GM Lanuza, T Velasquez, B Shanks, ... Neuron 60 (1), 84-96	2008
Expression of Robo/Slit and Semaphorin/Plexin/Neuropilin family members in the developing hypothalamic paraventricular and supraoptic nuclei C Xu, CM Fan Gene Expression Patterns 8 (7-8), 502-507	2008
Separate Necdin domains bind ARNT2 and HIF1α and repress transcription ER Friedman, CM Fan Biochemical and biophysical research communications 363 (1), 113-118	2007
The role of Gas1 in embryonic development and its implications for human disease DC Martinelli, CM Fan Cell Cycle 6 (21), 2650-2655	2007
Genetic interactions between Gas1 and Shh during early craniofacial development M Seppala, CM Fan, M Depew, P Sharpe, M Cobourne Genetical Research 89 (3)	2007
Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog M Seppala, MJ Depew, DC Martinelli, CM Fan, PT Sharpe, MT Cobourne The Journal of clinical investigation 117 (6), 1575-1584	2007
Gas1 extends the range of Hedgehog action by facilitating its signaling DC Martinelli, CM Fan Genes & development 21 (10), 1231-1243	2007
Allocation of Paraventricular and Supraoptic Neurons Requires Sim1 Function: A Role for a Sim1 Downstream Gene PlexinC1 C Xu, CM Fan Molecular Endocrinology 21 (5), 1234-1245	2007
Targeting gene expression in the mouse somite: Adenovirus‐mediated gene delivery and whole embryo culture AE Chen, CM Fan genesis 42 (2), 71-76	2005
Protein kinase A signalling via CREB controls myogenesis induced by Wnt proteins AE Chen, DD Ginty, CM Fan Nature 433 (7023), 317-322	2005
WNT regulation of myogenesis requires PKA and CREB. A Chen, D Ginty, CM Fan DEVELOPMENTAL BIOLOGY 271 (2), 552-552	2004
Sim2 Contributes to Neuroendocrine Hormone Gene Expression in the Anterior Hypothalamus E Goshu, H Jin, J Lovejoy, JF Marion, JL Michaud, CM Fan Molecular Endocrinology 18 (5), 1251-1262	2004
Interplays of Gli2 and Gli3 and their requirement in mediating Shh-dependent sclerotome induction L Buttitta, R Mo, CC Hui, CM Fan Development 130 (25), 6233-6243	2003
Identification of the downstream targets of SIM1 and ARNT2, a pair of transcription factors essential for neuroendocrine cell differentiation C Liu, E Goshu, A Wells, CM Fan Journal of Biological Chemistry 278 (45), 44857-44867	2003
GLI2 and GLI3 are required for SHH depedent sclerotome induction. L Buttitta, CC Hui, CM Fan DEVELOPMENTAL BIOLOGY 259 (2), 569-569	2003
Microarray analysis of somitogenesis reveals novel targets of different WNT signaling pathways in the somitic mesoderm L Buttitta, TS Tanaka, AE Chen, MSH Ko, CM Fan Developmental biology 258 (1), 91-104	2003
MOLECULAR BASIS OF CELL AND DEVELOPMENTAL BIOLOGY-Identification of the Downstream Targets of SIM1 and ARNT2, a Pair of Transcription Factors Essential for Neuroendocrine Cell … C Liu, E Goshu, A Wells, CM Fan Journal of Biological Chemistry 278 (45), 44857-44867	2003
Hormones, Obesity, Learning, and Breathing — the Many Functions of Mammalian Single-Minded Genes CM Fan PAS Proteins: Regulators and Sensors of Development and Physiology, 205-230	2003
Growth arrest specific gene 1: a fuel for driving growth in the cerebellum G Marques, CM Fan The Cerebellum 1 (4), 259-263	2002
Growth arrest specific gene 1 acts as a region-specific mediator of the Fgf10/Fgf8 regulatory loop in the limb Y Liu, C Liu, Y Yamada, CM Fan Development 129 (22), 5289-5300	2002
Nuclear factors associated with transcriptional regulation D Baltimore, R Sen, PA Sharp, H Singh, L Staudt, JH LeBowitz, ... US Patent 6,410,516	2002
Sim2 mutants have developmental defects not overlapping with those of Sim1 mutants E Goshu, H Jin, R Fasnacht, M Sepenski, JL Michaud, CM Fan Molecular and cellular biology 22 (12), 4147-4157	2002
Evidence that the WNT-inducible growth arrest-specific gene 1 encodes an antagonist of sonic hedgehog signaling in the somite CS Lee, L Buttitta, CM Fan Proceedings of the National Academy of Sciences 98 (20), 11347-11352	2001
Growth Arrest Specific Gene 1 Is a Positive Growth Regulator for the Cerebellum Y Liu, NR May, CM Fan Developmental biology 236 (1), 30-45	2001
Transdifferentiation of the ventral retinal pigmented epithelium to neural retina in the growth arrest specific gene 1 mutant CS Lee, NR May, CM Fan Developmental biology 236 (1), 17-29	2001
Gene expression during somitogenesis. LA Buttitta, TS Tanaka, MS Ko, CM Fan DEVELOPMENTAL BIOLOGY 235 (1), 268-268	2001
Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus JL Michaud, F Boucher, A Melnyk, F Gauthier, E Goshu, E Lévy, ... Human molecular genetics 10 (14), 1465-1473	2001
Embryonic expression patterns of the mouse and chick Gas1 genes CS Lee, CM Fan Mechanisms of development 101 (1-2), 293-297	2001
Members of the bHLH-PAS family regulate Shh transcription in forebrain regions of the mouse CNS DJ Epstein, L Martinu, JL Michaud, KM Losos, C Fan, AL Joyner Development 127 (21), 4701-4709	2000
ARNT2 acts as the dimerization partner of SIM1 for the development of the hypothalamus JL Michaud, C DeRossi, NR May, BC Holdener, CM Fan Mechanisms of development 90 (2), 253-261	2000
SHH-N upregulates Sfrp2 to mediate its competitive interaction with WNT1 and WNT4 in the somitic mesoderm CS Lee, LA Buttitta, NR May, A Kispert, CM Fan Development 127 (1), 109-118	2000
Remembrance of things PAS: regulation of development by bHLH–PAS proteins ST Crews, CM Fan Current opinion in genetics & development 9 (5), 580-587	1999
Development of neuroendocrine lineages requires the bHLH–PAS transcription factor SIM1 JL Michaud, T Rosenquist, NR May, CM Fan Genes & development 12 (20), 3264-3275	1998
Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite JA McMahon, S Takada, LB Zimmerman, CM Fan, RM Harland, ... Genes & development 12 (10), 1438-1452	1998
A role for WNT proteins in induction of dermomyotome CM Fan, CS Lee, M Tessier-Lavigne Developmental biology 191 (1), 160-165	1997
Single-minded—two genes, three chromosomes J Michaud, CM Fan Genome research 7 (6), 569-571	1997
Two murine homologs of the Drosophila single-minded protein that interact with the mouse aryl hydrocarbon receptor nuclear translocator protein MR Probst, CM Fan, M Tessier-Lavigne, O Hankinson Journal of Biological Chemistry 272 (7), 4451-4457	1997
Early deletion of neuromeres in Wnt‐1^‐/‐ mutant mice: Evaluation by morphological and molecular markers GS Mastick, CM Fan, M Tessier‐Lavigne, GN Serbedzija, AP McMahon, ... Journal of Comparative Neurology 374 (2), 246-258	1996
Lateral and axial signals involved in avian somite patterning: a role for BMP4 O Pourquié, CM Fan, M Coltey, E Hirsinger, Y Watanabe, C Bréant, ... Cell 84 (3), 461-471	1996
Expression Patterns of Two Murine Homologs ofDrosophila Single-MindedSuggest Possible Roles in Embryonic Patterning and in the Pathogenesis of Down Syndrome CM Fan, E Kuwana, A Bulfone, CF Fletcher, NG Copeland, NA Jenkins, ... Molecular and Cellular Neuroscience 7 (1), 1-16	1996
Physical mapping of the holoprosencephaly critical region in 21q22. 3, exclusion of SIM2 as a candidate gene for holoprosencephaly, and mapping of SIM2 to a region of … M Muenke, LJ Bone, HF Mitchell, I Hart, K Walton, K Hall-Johnson, ... American journal of human genetics 57 (5), 1074	1995
Long-range sclerotome induction by sonic hedgehog: direct role of the amino-terminal cleavage product and modulation by the cyclic AMP signaling pathway CM Fan, JA Porter, C Chiang, DT Chang, PA Beachy, M Tessier-Lavigne Cell 81 (3), 457-465	1995
Patterning of mammalian somites by surface ectoderm and notochord: evidence for sclerotome induction by a hedgehog homolog CM Fan, M Tessier-Lavigne Cell 79 (7), 1175-1186	1994
DORSOVENTRAL PATTERNING OF MAMMALIAN SOMITES-A ROLE FOR EPIDERMIS IN PATTERNING THE DERMOMYOTOME CM FAN, M TESSIERLAVIGNE JOURNAL OF CELLULAR BIOCHEMISTRY, 476-476	1994
Positive and Negative Control of Human Interferon- Gene Expression T Maniatis, LA Whittemore, W Du, CM Fan COLD SPRING HARBOR MONOGRAPH SERIES 22, 1193-1193	1993
Generation of p50 subunit of NF-k B by processing of p105 through an ATP-dependent pathway CM Fan, T Maniatis Nature 354 (6352), 395-398	1991
lymphoma c-myc alleles DP Lane, S Benchimol, P Pondaven, L Meijer, D Beach, RA Firtel, ... GENES & DEVELOPMENT	1990
A DNA-binding protein containing two widely separated zinc finger motifs that recognize the same DNA sequence. CM Fan, T Maniatis Genes & development 4 (1), 29-42	1990
The involvement of NF-κB in β-interferon gene regulation reveals its role as widely inducible mediator of signal transduction MJ Lenardo, CM Fan, T Maniatis, D Baltimore Cell 57 (2), 287-294	1989
Two different virus‐inducible elements are required for human beta‐interferon gene regulation. CM Fan, T Maniatis The EMBO Journal 8 (1), 101-110	1989

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