FGF Notes

by

Larry P. Taylor, Ph. D.

 

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Molecular & Behavioral Neuroscience Institute

The University of Michigan

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FGF Site: FGF Intro     Nomenclature     References     FGF Sequences     FGFR Sequences   

 

 

Jump To:  FGF 1   FGF 2   FGF 3   FGF 4   FGF 5   FGF 6   FGF 7   FGF 8   FGF 9   FGF 10

 

FGF 11   FGF 12   FGF 13   FGF 14   FGF 15   FGF 16   FGF 17   FGF 18   FGF 19   FGF 20

 

FGF 21   FGF 22   FGF 23          FGFRs

 

Fibroblast Growth Factors (FGF's) belong to the cytokine family of proteins that have a common beta trefoil core (typically 12 separate beta sheets with a total of approximately 120 amino acid residues folded into the trefoil configuration), Although some of the FGF's do induce fibroblast proliferation, the original FGF molecule (FGF 2 or basic FGF)  also induces proliferation of endothelial cells, chondrocytes, smooth muscle cells, melanocytes, and other cells. It can also promote adipocyte differentiation, induce macrophage and fibroblast IL-6 production, stimulate astrocyte migration, as well as prolonging neuronal survival. FGF's have also been implicated in development, angiogenesis, hematopoiesis, and tumorigenesis.

General Observations

FGF molecules are derived from the translation of three exons which yields species of  molecular weights ranging from 7 kDa (FGF 1) to 38 kDa (FGF 5) with amino acid residues varying from 60 amino acids  (a FGF 1 splice variant) to 288 amino acids  (a FGF 2 variant).  Comparison  of the aligned sequences shows amino acid identity varies from 17% to 72% (20-30% on average), with Clustal X defining seven homologous subfamilies. (see sequences).

Many FGF molecules show N-terminal structural variants prior to the common beta trefoil core. This is a result of several factors including:

FGF 1

UniProtKB/Swiss-Prot  P05230  Entrez Gene FGF1  ihop FGF1    PDB Sum 1axm 1dzc  Kinemages 1AXM  1DZC

 

FGF 1 (acidic FGF, FGFa, ECGF, or HBGF 1) is a 17-18 kDa  (155 amino acids) non-glycosylated protein. FGF 1 has no definitive signal sequence. FGF 1 is released as a disulfide-linked dimer via an ATP-dependent process involving synaptotagmin-1. So, biological activity (heparin affinity)  is contingent upon reduction of the FGF dimer disulphide link to form the FGF 1 monomer. The bioactive FGF 1 is stored on/or in the glycosaminoglycan component/heparin sulfate (HS) of the extra-cellular matrix. FGF 1 interacts with both cellular surface HS and any of the  FGF receptors: FGFR 1 ( IIIb & IIIc),  FGFR 2, (IIIb & IIIc), FGFR 3, (IIIb & IIIc), and FGFR 4. Since FGF 1 binds to all known FGF receptors with high affinity, it is considered to be the universal ligand for FGF receptors.

Residues 22 to 28 of FGF 1 contain a nuclear localization sequence ((NLS): NYKKPLK ). However, the route to the nucleus and any nuclear activity is unclear.

The mitogenic activity of FGF 1 is blocked by the synthetic peptide Ac-VYMSPF-NH2

The human FGF 1 sequence has a  96% amino acid identity with the mouse sequence and a 95%  identity with the FGF 1 rat sequence.

Cells known to express FGF 1 include intestinal enterochromaffin cells, renal proximal tubule cells, smooth muscle cells, neurons, hepatocytes, skeletal muscle cells, endothelial cells and macrophages, keratinocytes and fibroblasts. FGF 1 is a key component in fat tissue development.

FGF 2

UniProtKB/Swiss-Prot  P09038  Entrez Gene FGF2  ihop FGF2  PDB Sum 1bff  4fgf  Protein Reference  FGF 2  Kinemage 1BFF 

 

FGF 2 (basic FGF, HBGF 2, and EDGF) is an 18 kDa (155 amino acids), non-glycosylated protein. However,  there are at least four alternative leucine start codons that can provide N-terminal extensions of the FGF core resulting in isoforms of  22 kDa (196 amino acids), 22.5 kDa (201 amino acids), 24 kDa (210 amino acids) and 34 kDa (288 amino acids). The N-terminal extensions alter biological activity in a tissue-specific fashion. For example, the 18 kDa FGF 2 up-regulates t-PA, while the 24 kDa FGF 2 down-regulates t-PA  in pancreatic carcinoma cells. In general, the 155 residue FGF 2 is considered cytoplasmic, while the longer N-terminal extension proteins are considered to be nuclear. FGF 2 is secreted as a monomer which is stored on either the cell surface HS or matrix glycosaminoglycans. FGF 2 binds with high affinity to FGF receptors FGFR 1 ( IIIb & IIIc), FGFR 2 (IIIc), FGFR 3 (IIIc) and FGFR 4.

FGF 2 is secreted as a monomer, but it aggregates into non-covalent clusters on the HS surface that dimerize to activate FGF receptors. This dimerization process may be regulated by ribosylation of the low-affinity receptor binding region  (residues 106-120) of the core FGF 2.

FGF 2 was the first growth factor isolated. It was termed basic FGF because of its high isoelectric point.

N-terminal extensions of FGF 2 are associated with entry into the nucleus which results in casein kinase II, a component of  cell-cycle proliferation, activation, . 

Human 155 residue FGF 2 has 97%  amino acid identity to both mouse and rat FGF 2. 

Cells known to express FGF 2 include visceral and vascular smooth muscle cells, cardiac muscle cells, lining epithelium of the colon and bronchus, neurons, plus cerebellar Purkinjie cells, megakaryocytes and platelets, endothelial cells, mast cells, glomerular parietal epithelial cells and podocytes, astrocytes, CD4 and CD8 T cells, fibroblasts , and numerous embryonic mesodermal and neuroectodermal tissues.

FGF 3

 

 UniProtKB/Swiss-Prot  P11487     Entrez Gene FGF3     ihop FGF 3

FGF 3 (Int-2) is a 28-32 kDa (222 amino acids) glycoprotein that contains several protein motifs:  a 17 residue signal sequence, a 24 amino acid  N-terminal and an 18 amino acid C-terminal NLS. FGF 3 binds with high affinity to FGF receptors  FGFR 1(IIIb) and FGFR2 (IIIb).

Secreted FGF 3 can induce DNA synthesis, but nuclear FGF 3 has an inhibitory effect on cell proliferation. The nuclear form of FGF 3 inhibits cell proliferation by interfering with ribosomal biogenesis.

Human FGF 3 has 81 %  amino acid identity to mouse FGF 3 over the entire methionine-initiated coding region, but the mouse sequence has an additional 274 amino acids N-terminal extension resulting  from the use of an alternative leucine start sites.

Cells known to express FGF 3 include developmental cells and tumors; normal adult cells appear not to express FGF 3. Embryonic cells and structures expressing FGF 3 include primitive streak mesoderm,  pharyngeal pouch endoderm, pharyngeal arch ectoderm and hindbrain neuroepithelium, and sensory cells of the inner ear. Tumors known to express FGF 3 include breast carcinomas and colon cancer cell lines.

FGF 4

UniProtKB/Swiss-Prot  P08620  Entrez Gene FGF4  ihop  FGF4  PDB Sum 1ijt  Kinemage 1IJT

FGF 4 (kFGF, Kaposi FGF, hst-1) is a 22 kDa (176 amino acids) glycoprotein that is the product of a developmentally-regulated gene. The molecule is synthesized as a 206 amino acid  precursor that contains an approximately 30 amino acid signal sequence, plus two heparin-binding motifs (residues 51-55 and 140-143). The heparin-binding sites regulate FGF 4 activity. At low (physiological) heparin concentrations, FGF 4 only binds to FGFR 2 (IIIc),  but at high heparin concentrations it can also bind to FGF receptors FGFR 1, FGFR 3 (IIIc), and FGFR-4.

FGF 4 synonyms were derived from the compounds isolation from the tumor cells of human stomach cancer (/hst-1/hst) and  Kaposi's sarcoma (kFGF).

There is 87% amino acid identity between human and mouse FGF 4. 

Cells known to express FGF 4 include tumor cells and embryonic cells primitive streak mesoderm, molar enamel knot epithelium, apical ridge ectoderm, mature somitic myotome,  the ectoderm of day 4 blastocysts,  and cells of the notochord anterior to Hensen's node.

FGF 5

UniProtKB/Swiss-Prot  P12034     Entrez Gene FGF5     ihop FGF5

FGF 5 is a 32-38 kDa (268 amino acids)  glycoprotein that was originally discovered in 3T3 fibroblasts. Human FGF 5 is synthesized as a  precursor that contains a 17 amino acid signal sequence and a 251 amino acid mature peptide. FGF 5 contains both N- and O-linked glycosylations. FGF 5 has high affinity for FGF receptors FGFR 1 (IIIc) and  FGFR 2 (IIIc).

FGF 5 is mitogenic for both endothelial cells and fibroblasts. Besides the 268 amino acid  precursor form, the human gene also produces a glycosylated alternate splice form that is 18 kDa (123 residues). This molecule is found in the brain and has a concentration dependent partial agonist/antagonist activity.

Human  FGF 5  has 85 %  amino acid identity to mouse and  84 % amino acid identity with rat FGF 5. 

Both embryonic and adult cells are known to express FGF 5. In the embryo, FGF 5 is found in the myotome, lateral splanchnic mesoderm and acoustic ganglia. In the adult, it also occurs in thalamic reticular and hippocampal CA3 neurons, skeletal muscle, and pancreatic ß-cells, ductal cells, fibroblasts and acinar cells.

FGF 6

UniProtKB/Swiss-Prot P10767     Entrez Gene FGF6     ihop FGF6

FGF 6, (hst-2) was originally identified as the product of an FGF 4/hst homologous gene. In humans, FGF 6 is secreted as a 25 kDa glycosylated polypeptide. FGF 6 has three potential methionine start codons with possible peptides of 208, 198, or 175 amino acids. The preferred peptide is 198 residues (with a 27 residue signal region). FGF 6 binds with high affinity to FGF receptors FGFR 1 (IIIc), FGFR 2 (IIIc), and FGFR 4.

Mouse FGF 6 shows multiple N-terminal forms, varying from 171 to 136 amino acids. The 171 residue form is highly glycosylated and a  potent mitogenic agent for endothelial cells.

FGF 6 displays  in vivo anti-tumor activity in medulloblastoma cells

Human FGF 6 has a  93% amino acid identity to mouse FGF 6. 

FGF 6 occurs in skeletal muscle tissue; primarily in the myotomes and adult skeletal muscle cells.

FGF 7

UniProtKB/Swiss-Prot P21781  Entrez Gene FGF7  ihop FGF7  PDB Sum 1qqk  Kinemage 1QQK

Human FGF 7 (keratinocyte growth factor or KGF), is a 28 kDa secreted glycoprotein that has a target specificity restricted to epithelium. The molecule is synthesized as a 194 amino acid precursor with a  31 amino acid signal sequence. Heparin is required for KGFR activation.  Although FGF 7 is glycosylated, non-glycosylated KGF shows higher mitogenic activity than native FGF 7. FGF 7 binds with high affinity to FGFR-2 (IIIb). 

Human FGF 7 has a 96% amino acid identity to mouse FGF 7 and 92% amino acid identity to rat FGF 7. 

Increased levels of  FGF 7 by buccal mucosal fibroblasts may partly be responsible for the faster wound healing with less scar formation in the oral cavity.

FGF 7 may be a significant factor in lung development, inflammation, and repair.

Adult cells known to express FGF 7 include fibroblasts, γδ T cells, smooth muscle cells,  and ovarian theca cells. In the embryo, KGF is found  throughout the mesenchyme.

FGF 8

UniProtKB/Swiss-Prot  P55075     Entrez Gene FGF8    ihop FGF8

FGF 8 (AIGF, androgen-induced growth factor), is secreted as a 28-32 kDa glycoprotein with two alternate splice forms. While most FGF  molecules are derived from three exons, FGF 8 has its first exon split into at least four segments followed by the common exons 2 and 3. This gives rise to multiple splice variants (at least eight isoforms in mouse and four in human).  In mouse, the eight isoforms are labeled 8a through 8h (8b is the 28 kDa AIGF), with isoforms ranging from 204 amino acids (8a) to 298 acids (8h).  All the isoforms are identical within the C-terminal 142 amino acids as exon 2 (35 residues) and exon 3 (107 residues) are invariant.  In the variable N-terminus (62 to 156 amino acids in length), a constant 22 amino acid signal sequence is always present. However, differences occur in the number of potential N-linked glycosylation sites. Human FGF 8 is limited to four isoforms due to the existence of a stop codon in the second mini-exon. Only the 8a (204 amino acids), 8b (215 amino acids), 8e (233 amino acids) and 8f (244 amino acids)  isoforms are expressed. 

Mouse and human 8a and 8b isoforms are 100% identical, while the 8e and 8f isoforms are 98% identical. The isoforms have different affinities for various receptor isoforms. For example, 8a activates no known receptor, 8b activates FGFR 2 (IIIc0, FGFR 3 (IIIc),  and FGFR 4, while 8e activates FGFR 3 (IIIc) and FGFR 4; no FGF 8 isoform activates a IIIb form or FGFR 1.

FGF 8b may be of prognostic value in prostate cancer.

In the fetus, regions known to express FGF 8 include the embryonic infundibulum, the apical ectodermal ridge of the limb bud and oral epithelium of the first bronchial arch, and the pre-primitive streak embryonic ectoderm, nephrogenic cords, Bowman's capsule and developing labyrinth. In the adult, it is found in prespermatogonia and antral follicles of the ovary.

FGF 9

UniProtKB/Swiss-Prot P31371  Entrez Gene FGF9  ihop FGF9  PDB Sum  1ihk  1g82  Kinemages 1IJK  1G82

 

Human FGF 9 (GAF or glia-activating factor) is a 30 kDa secreted glycoprotein .The molecule is synthesized as a 208 amino acid  precursor that has no definitive signal sequence. FGF 9 may exist in multiple N-terminally truncated forms ranging from 30 kDa (205 amino acids) , 29 kDa (197 amino acids)  or 25 kDa (175 amino acids). It is unknown if these species are an artifact of isolation or naturally-occurring, proteolytically processed forms. 

 

FGF 9 has unique (compared to other FGF species) C and N-terminal alpha helical extensions that allow self-dimerization.

 

FGF 9 binds with high affinity to FGF receptors  FGFR 2 (IIIc), FGFR 3 ( IIIb & IIIc), and FGFR 4.

 

Human FGF 9 is  98% identical to mouse and 100% identical to rat FGF 9.

 

FGF 9  is primarily involved with  nervous tissue. Cells known to express FGF 9 include prostatic stromal cells,  neurons, astrocytes and oligodendrocytes,  embryonic oral epithelium of the first bronchial arch and primary enamel knot and fetal skeletal myoblasts, ventricular myocardium, gut lumenal epithelium and the olfactory bulb.

FGF 10

UniProtKB/Swiss-Prot  O15520     Entrez Gene FGF10     ihop FGF10  Protein Reference FGF 10

FGF 10 is synthesized as a 209 amino acid precursor that contains an unusually long signal sequence (35 amino acids) and an N-terminal serine repeat motif. Although the molecule is presumed to be secreted, it does not appear free unless exposed to heparin, suggesting it is sequestered on cell surfaces or within the extracellular matrix. 

FGF 10 binds with high affinity to FGF receptors  FGFR 1 (IIIb),  and FGFR 2 (IIIb).

FGF 10 mRNA is over expressed in a subset of human breast carcinomas.

FGF 10 up regulates an ATPase via the MAPK pathway.

There is 94 % amino acid identity within the mature segments of human and mouse FGF 10. There is 100% amino acid identity within the mature segments of human and rat FGF 10, with the rat exhibiting an extended repeat of serines in the N-terminus (13 for rat vs. 5 for human).  In addition to the full-length molecule, rat FGF 10 has an alternate translation initiation methionine at position 42.

Cells known to express FGF 10 include fibroblasts and pre-adipocytes in the adult, plus lung mesenchyme, posterior limb mesoderm and mesenchyme associated with the development of the seminal vesicle and prostate in the fetus.

FGF 11

UniProtKB/Swiss-Prot Q92914      Entrez Gene FGF11     ihop FGF11

Human FGF 11 (FHF 3) was originally cloned from a human retinal cDNA library and found to encode a 225 amino acid protein with no signal sequence and a potential NLS. Mouse FGF 11 has two alternate splice forms; one 225 amino acids in length and another 165 amino acids in length.

FGF 11 was originally known as FHF 3 (fibroblast homologous factor) 

Human FGF 11 has  97% amino acid identity with mouse FGF 11. 

FGF 11  is found throughout the embryo at various stages.

FGF 12

 

UniProtKB/Swiss-Prot  P61328  Entrez Gene FGF12  ihop FGF12  PDB Sum 1q1u  Protein Reference FGF 12  Kinemage 1Q1U

 

FGF 12  (FHF 1) is a 243 amino acid protein associated with a variety of developmental structures. The molecule has two N-terminal sequences at residues 11-18 and 28-38 that qualify as a bipartite NLS, and a secondary NLS at residues 56-68. 

 

Human and mouse is almost 100% amino acid identical in the 243 amino acid long form (FGF 12A). In both mouse and human, there is at least one other alternatively spliced short form of 181 amino acids (FGF 12B). This form does not possess an NLS and its function is unknown.

 

In the embryo, cells known to express FGF 12 include mesenchyme surrounding sites of skeletal formation, glomeruli, and atrial myocardium; in the adult, FGF 12 message is found in various regions.

FGF 13

UniProtKB/Swiss-Prot  Q92913     Entrez Gene FGF13     ihop FGF13

Human and mouse FGF 13 (FHF 2) are 245 amino acid proteins that arise from genes that show N-terminal alternate splicing. In human and mouse, transcripts for 245 amino acids, 199 amino acids, 226 amino acids, 192 amino acids and 255 amino acids  have been identified.

There is an almost complete cross-species amino acid identity among all splice forms (> 98%). 

FGF 13 has been identified in fetal ependyma, dorsal root and cranial ganglia, both atrial and ventricular myocardium, and in renal collecting duct-associated mesenchyme.

FGF 14

UniProtKB/Swiss-Prot  Q92915     Entrez Gene FGF14     ihop FGF14

Human FGF 14 (FHF 4) is a 245 amino acid  polypeptide that contains no signal sequence, but possesses a bipartite NLS with a secondary signal motif. 

There are three splice variants: a 245 amino acid  (FGF 14A), a  252 amino acid  (FGF 14B), and a 163 amino acid (mouse only, FGF 14C) isoform. Splice forms A and B are N -terminal extensions of the common to all 163 amino acids of the C-terminal sequence of FGF 14.

FGF14  modulates CNS Nav channel activity.

A mutation in the FGF 14 gene is associated with autosomal dominant cerebral ataxia

Embryonic regions known to express FGF 14 include central nervous system zones that contain migrating neurons and glia, the aortic arch and its immediate branches, granule cells of the cerebellum, and the mammillary nuclei whereas adult cells known to express FGF 14(C) are limited to spermatocytes.

FGF 15 (Mouse)

UniProtKB/Swiss-Prot  O35622      Entrez Gene Fgf15     ihop FGF15

This molecule is only known to exist in mouse and consists of  218 amino acids with a 23 amino acid signal sequence..

FGF 15 represses the gene encoding cholesterol 7alpha-hydroxylase (CYP7A1), which catalyzes the first and rate-limiting step in the classical bile acid synthetic pathway.

FGF 15 is found in the optic vesicle, a subset of progenitor cells of neural retina, and emerging ganglion and amacrine cells during retinogenesis

FGF 16

UniProtKB/Swiss-Prot  O43320     Entrez Gene FGF16     ihop FGF16

Human FGF 16 is a 26 kDa, (207 amino acid) polypeptide that shows no identifiable signal sequence. 

Human FGF 16 is 96 % identical to mouse and rat FGF 16.

FGF 16 is expressed by brown adipocytes.

FGF 17

UniProtKB/Swiss-Prot  O60258     Entrez Gene FGF17     ihop FGF17

FGF 17, like FGF 8, has three potential mini-exons substituting for the standard exon of FGF proteins. Although this creates a potential for  multiple isoforms, only one human form (FGF 17 B; 216 amino acids)  is known; the mouse has three isoforms termed 17A, 17B, and 17C.. 

Human FGF 17B shares 93% amino acid  identity with mouse and rat FGF 17B sequences.

FGF 17 has been found in the embryo at the midbrain-hindbrain junction, in the telencephalon-diencephalon transition, in the smooth muscle of major artery walls, in chondrocytes, osteoblast precursors, and in mesenchymal cells.

FGF 18

UniProtKB/Swiss-Prot  O76093     Entrez Gene FGF18     ihop FGF18

Human FGF 18 is a 31 kDa  (207 amino acids) that contains a 26 residue signal sequence with a 181 amino acid mature segment. 

Human FGF 18 shares 99% amino acid  identity with both mouse and rat FGF 18.

FGF 18 appears to be involved in lung physiology as it is present in both adult and fetal lung respiratory system.

FGF 19

UniProtKB/Swiss-Prot O95750  Entrez Gene FGF19  ihop FGF19  PDB Sum  1pwa  1pwa  Kinemage 1PWA

Human FGF 19 216 amino acids in length with a 22 amino acid signal sequence.

FGF 19 has 2 disulphide bonds.

FGF 19 increases metabolic rate with a corresponding increase in fatty acid oxidation

Embryonic regions known to express FGF19 include skin, cartilage, retina, gall bladder and small intestine.

FGF 20

UniProtKB/Swiss-Prot  Q9NP95     Entrez Gene FGF20     ihop FGF20

Human FGF 20 (XFGF) is a 23 kDa, 211 amino acid  polypeptide that contains no signal sequence. 

FGF 20 has 72% amino acid identity  with FGF 9, suggesting similar properties. 

FGF 20  polymorphisms and haplotypes are associated Parkinson's disease

FGF 20 is preferentially expressed in colorectal cancer

FGF 21

UniProtKB/Swiss-Prot  Q9NSA1     Entrez Gene FGF21     ihop FGF21

FGF 21 is a 19.6 kDa (170 amino acid)  protein.

Human FGF 21 is 75%  identical with mouse FGF 21. 

In mouse, FGF 21  is expressed preferentially in liver.

FGF 22

UniProtKB/Swiss-Prot Q9HCT0     Entrez Gene FGF22     ihop FGF22

FGF 22 is a 23 kDa ( 209 amino acid)  protein with a 22 amino acid signal sequence. The mature protein is 148 residues. .

FGF-22,is preferentially expressed in the inner root sheath of the hair follicle.

FGF 23

UniProtKB/Swiss-Prot  Q9GZV9     Entrez Gene FGF23     ihop FGF23

FGF 23 precursor is 27.9 kDa (251 amino acid)  protein with  24 amino acid residue signal sequence. The mature protein is 227 residues.

FGF 23 plays a role in phosphate uptake in intestine and phosphate reabsorption in kidney.

FGF 23 is preferentially Expressed in the Ventrolateral Thalamic Nucleus of the Brain

 

Gene Sites for Human FGF Receptors

FGFR 1  UniProt     Entrez     iHOP     ProteinReference

FGFR 2  UniProt     Entrez     iHOP     Protein Reference

FGFR 3  UniProt     Entrez     iHOP     Protein Reference

 FGFR 4  UniProt     Entrez     iHOP    Protein Reference

FGFR 5  UniProt     Entrez     iHOP     Protein Reference

  FGFR 6  Entrez    iHOP

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Jump To:  FGF 1   FGF 2   FGF 3   FGF 4   FGF 5   FGF 6   FGF 7   FGF 8   FGF 9  FGF 10

 

FGF 11   FGF 12   FGF 13   FGF 14   FGF 15   FGF 16   FGF 17   FGF 18   FGF 19   FGF 20

 

FGF 21   FGF 22   FGF 23

 

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FGF Site: FGF Intro     Nomenclature     Notes      References     FGF Sequences     FGFR Sequences 

 

Copyright 2005-2020 by Larry P. Taylor
Molecular & Behavioral Neuroscience Institute
The University of Michigan

All Rights Reserved

Supported by the Pritzker Neuropsychiatric Disorders Research Consortium, and by NIH Grant 5 P01 MH42251, Conte Center Grant #L99MH60398, RO1 DA13386 and the Office of Naval Research (ONR) N00014-02-1-0879 to Huda Akil & Stanley J. Watson. at the Molecular & Behavioral Neuroscience Institute.